3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands

ABSTRACT

There are disclosed compounds of the formula  
                 
 
     or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation in part of U.S. applicationSer. No. 10/241326 filed Sep. 11, 2002, which in turn is a continuationin part of U.S. application Ser. No. 10/208412 filed Jul. 30, 2002,which in turn is a continuation in part of U.S. application Ser. No.10/122841 filed Apr. 15, 2002, which in turn claims the benefit U.S.Provisional Application 60/284,026, filed Apr. 16, 2001, the disclosuresof which are incorporated herein by reference thereto.

FIELD OF THE INVENTION

[0002] The present invention relates to novel substitutedcyclobutenedione compounds, pharmaceutical compositions containing thecompounds, and the use of the compounds and formulations in treating CXCchemokine-mediated diseases.

BACKGROUND OF THE INVENTION

[0003] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T-cells, eosinophils,basophils, neutrophils and endothelial cells to sites of inflammationand tumor growth. There are two main classes of chemokines, theCXC-chemokines and the CC-chemokines. The class depends on whether thefirst two cystepnes are separated by a single amino acid(CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokinesinclude interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1),neutrophil-activating protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78,GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1α, MIP-2β,monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin.Individual members of the chemokine families are known to be bound by atleast one chemokine receptor, with CXC-chemokines generally bound bymembers of the CXCR class of receptors, and CC-chemokines by members ofthe CCR class of receptors. For example, IL-8 is bound by the CXCR-1 andCXCR-2 receptors.

[0004] Since CXC-chemokines promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);Donnely et al., Lancet 341, 643(1993).

[0005] ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, NAP-2, andENA-78 (Strieter et al. 1995 JBC 270 p. 27348-57) have also beenimplicated in the induction of tumor angiogenesis (new blood vesselgrowth). All of these chemokines are believed to exert their actions bybinding to the 7 transmembrane G-protein coupled receptor CXCR2 (alsoknown as IL-8RB), while IL-8 also binds CXCR1 (also known as IL-8RA).Thus, their angiogenic activity is due to their binding to andactivation of CXCR2, and possible CXCR1 for IL-8, expressed on thesurface of vascular endothelial cells (ECs) in surrounding vessels.

[0006] Many different types of tumors have been shown to produce ELRCXCchemokines and their production has been correlated with a moreaggressive phenotype (Inoue et al. 2000 Clin Cancer Res 6 p. 2104-2119)and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p.447-454).Chemokines are potent chemotactic factors and the ELRCXC chemokines havebeen shown to induce EC chemotaxis. Thus, these chemokines probablyinduce chemotaxis of endothelial cells toward their site of productionin the tumor. This may be a critical step in the induction ofangiogenesis by the tumor. Inhibitors of CXCR2 or dual inhibitors ofCXCR2 and CXCR1 will inhibit the angiogenic activity of the ELRCXCchemokines and therefore block the growth of the tumor. This anti-tumoractivity has been demonstrated for antibodies to IL-8 (Arenberg et al.1996 J Clin Invest 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J ClinInvest 102 p.465-72), and GROα (Haghnegahdar et al. J. Leukoc Biology2000 67 p. 53-62).

[0007] Many tumor cells have also been shown to express CXCR2 and thustumor cells may also stimulate their own growth when they secrete ELRCXCchemokines. Thus, along with decreasing angiogenesis, inhibitors ofCXCR2 may directly inhibit the growth of tumor cells.

[0008] Hence, the CXC-chemokine receptors represent promising targetsfor the development of novel anti-inflammatory and anti-tumor agents.

[0009] There remains a need for compounds that are capable of modulatingactivity at CXC-chemokine receptors. For example, conditions associatedwith an increase in IL-8 production (which is responsible for chemotaxisof neutrophil and T-cell subsets into the inflammatory site and growthof tumors) would benefit by compounds that are inhibitors of IL-8receptor binding.

SUMMARY OF THE INVENTION

[0010] This invention provides a method of treating a chemokine mediateddisease in a patient in need of such treatment comprising administeringto said patient an effective amount of a compound of formula IA, asdescribed below

[0011] This invention also provides a method of treating cancer in apatient in need of such treatment comprising administering to saidpatient an effective amount of a compound of formula IA, as describedbelow.

[0012] This invention also provides a method of treating cancer in apatient in need of such treatment comprising administering to saidpatient an effective amount of a compound of formula IA, as describedbelow, concurrently or sequentially with: (a) a microtubule affectingagent, or (b) an antineoplastic agent, or (c) an anti-angiogenesisagent, or (d) a VEGF receptor kinase inhibitor, or (e) antibodiesagainst the VEGF receptor, or (f) interferon, and/or g) radiation.

[0013] This invention also provides a method of inhibiting angiogenesis,in a patient in need of such treatment, comprising administering to saidpatient an effective amount of at least one compound of formula IA, asdescribed below.

[0014] This invention also provides a method of treating angiogenicocular disease (e.g., ocular inflammation, retinopathy of prematurity,diabetic retinopathy, macular degeneration with the wet type preferredand corneal neovascularization) in a patient in need of such treatment,comprising administering to said patient an effective amount of at leastone compound of formula IA, as described below.

[0015] This invention also provides a method of treating a diseaseselected from the group consisting of: gingivitis, respiratory viruses,herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma associatedvirus and atherosclerosis, in a patient in need of such treatment,comprising administering to said patient an effective amount of at leastone compound of formula IA, as described below.

[0016] This invention also provides a method of treating acuteinflammatory pain, in a patient in need of such treatment, comprisingadministering to said patient an effective amount of at least onecompound of formula IA, as described below.

[0017] This invention also provides a method of treating chronicinflammatory pain, in a patient in need of such treatment, comprisingadministering to said patient an effective amount of at least onecompound of formula IA, as described below.

[0018] This invention also provides a method of treating acuteneuropathic pain, in a patient in need of such treatment, comprisingadministering to said patient an effective amount of at least onecompound of formula IA, as described below.

[0019] This invention also provides a method of treating chronicneuropathic pain, in a patient in need of such treatment, comprisingadministering to said patient an effective amount of at least onecompound of formula IA, as described below.

[0020] This invention also provides a method of treating COPD, in apatient in need of such treatment, comprising administering to saidpatient and effective amount of at least one compound of formula IA asdescribed below.

[0021] This invention also provides a method of treating acuteinflammation, in a patient in need of such treatment, comprisingadministering to said patient and effective amount of at least onecompound of formula IA as described below.

[0022] This invention also provides a method of treating chronicinflammation, in a patient in need of such treatment, comprisingadministering to said patient and effective amount of at least onecompound of formula IA as described below.

[0023] This invention also provides a method of treating rheumatoidarthritis, in a patient in need of such treatment, comprisingadministering to said patient and effective amount of at least onecompound of formula IA as described below.

[0024] This invention also provides novel compounds of formula IA, asdescribed below.

[0025] This invention also provides a pharmaceutical compositioncomprising at least one (e.g., 1-3, usually 1) compound of formula IA,as described below, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0026] When any variable occurs more than one time in any moiety, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

[0027] Unless indicated otherwise, the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. For example, the definition of “alkyl” also applies to the“alkyl” portion of “alkoxy”.

[0028] “At least one” represents, for example, 1, or 1-2, or 1-3.

[0029] “Patient” includes both human and other mammals, preferablyhuman.

[0030] “Mammal” includes a human being, and preferably means a humanbeing.

[0031] “Alkyl” means a straight or branched saturated hydrocarbon chainhaving 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, morepreferably 1 to 6 carbon atoms.

[0032] “Alkoxy” means an alkyl-O-group wherein alkyl is as definedabove. Non-limiting examples of alkoxy groups include: methoxy, ethoxy,n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety isthrough the ether oxygen.

[0033] “Alkenyl” means a straight or branched aliphatic hydrocarbongroup having at least one carbon-carbon double bond, and 2 to 20 carbonatoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 6carbon atoms. Non-limiting examples of alkenyl groups include: ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl.

[0034] “Alkynyl” means a straight or branched aliphatic hydrocarbongroup having at least one carbon-carbon triple bond, and 2 to 15 carbonatoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 4carbon atoms. Non-limiting examples of alkynyl groups include ethynyl,propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

[0035] “Aryl” means an aromatic monocyclic or multicyclic ring system,wherein at least one ring is aromatic, comprising about 6 to about 14carbon atoms, and preferably about 6 to about 10 carbon atoms.Non-limiting examples of suitable aryl groups include: phenyl, naphthyl,indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

[0036] “Arylalkyl” means an aryl group, as defined above, bound to analkyl group, as defined above, wherein the alkyl group is bound to theparent moiety. Non-limiting examples of suitable arylalkyl groupsinclude benzyl, phenethyl and naphthleneylmethyl.

[0037] “Cycloalkyl” means saturated carbocyclic rings having 3 to 10(e.g., 3 to 7) carbon atoms, preferably 5 to 10 carbon atoms, and morepreferably 5 to 7 carbon atoms, and having one to three rings.Non-limiting examples of cycloalkyl groups include: cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0038] “Cycloalkylalkyl” means a cycloalkyl group bound to the parentmoiety through an alkyl group. Non-limiting examples include:cyclopropylmethyl and cyclohexylmethyl.

[0039] “Cycloalkenyl” means a non-aromatic mono or multicyclic ringsystem comprising 3 to 10 carbon atoms, and preferably 5 to 10 carbonatoms, and having at least one carbon-carbon double bond. Preferredcycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples ofcycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,and norbornenyl.

[0040] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0041] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferredare fluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

[0042] “Haloalkyl” means an alkyl group as defined above wherein one ormore hydrogen atoms on the alkyl is replaced by a halo group definedabove.

[0043] “Heterocyclyl” or “heterocyclic” or “heterocycloalkyl” means anon-aromatic saturated monocyclic or multicyclic ring system (i.e., asaturated carbocyclic ring or ring system) comprising 3 to 10 ring atoms(e.g., 3 to 7 ring atoms), preferably 5 to 10 ring atoms, in which oneor more of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls have 5 to 6 ring atoms. The prefix aza, oxa orthia before the heterocyclyl root name means that at least a nitrogen,oxygen or sulfur atom, respectively, is present as a ring atom. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of monocyclic heterocyclyl rings include: piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,and tetrahydrothiopyranyl.

[0044] The term heterocyclic acidic functional group is intended toinclude groups such as, pyrrole, imidazole, triazole, tetrazole, and thelike.

[0045] “Heteroaryl” means an aromatic monocyclic or multicyclic ringsystem comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, inwhich one or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thiabefore the heteroaryl root name means that at least a nitrogen, oxygenor sulfur atom respectively, is present as a ring atom. A nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.Non-limiting examples of heteroaryls include: pyridyl, pyrazinyl,furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl,thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, and benzothiazolyl.

[0046] “Heteroarylalkyl” means a heteroaryl group, as defined above,bound to an alkyl group, as defined above, where the bond to the parentmoiety is through the alkyl group.

[0047] N-oxides can form on a tertiary nitrogen present in an Rsubstituent, or on ═N— in a heteroaryl ring substituent and are includedin the compounds of formula I.

[0048] The term “prodrug,” as used herein, represents compounds whichare rapidly transformed in vivo to the parent compound of the aboveformula, for example, by hydrolysis in blood. A thorough discussion isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

[0049] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0050] As used in the methods of this invention, “an effective amount”means a therapeutically acceptable amount (i.e., that amount whichprovides the desired therapeutic effective).

[0051] Also, as used herein, with reference to chemical structures orformulas, “Bn” represents benzyl, “Et” represents ethyl, “Me” representsmethyl, and “Ph” represents phenyl.

[0052] Representative embodiments of this invention are described below.The embodiments have been numbered for purposes of reference thereto.

[0053] The methods of this invention use a compound of formula IA:

[0054] and the pharmaceutically acceptable salts (e.g., sodium orcalcium salt) and solvates thereof, wherein:

[0055] A is selected from the group consisting of:

[0056] wherein the above rings of said A groups are substituted with 1to 6 substituents each independently selected from the group consistingof: R⁹ groups;

[0057] wherein one or both of the above rings of said A groups aresubstituted with 1 to 6 substituents each independently selected fromthe group consisting of: R⁹ groups;

[0058] wherein the above phenyl rings of said A groups are substitutedwith 1 to 3 substituents each independently selected from the groupconsisting of: R⁹ groups; and

[0059] B is selected from the group consisting of

[0060] n is 0 to 6;

[0061] p is 1 to 5;

[0062] X is O, NH, or S;

[0063] Z is 1 to 3;

[0064] R² is selected from the group consisting of: hydrogen, OH,—C(O)OH, —SH, —SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—NR¹³R¹⁴—C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, anunsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

[0065] each R³ and R⁴ is independently selected from the groupconsisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴,—SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl,

[0066] wherein there are 1 to 6 substituents on said substituted arylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups; and wherein there are 1 to 6 substituents onsaid substituted heteroaryl group and each substituent is independentlyselected from the group consisting of: R⁹ groups;

[0067] each R⁵ and R⁶ are the same or different and are independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkoxy,—CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

[0068] each R⁷ and R⁸ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstitutent is independently selected from the group consisting of:

[0069] a) halogen,

[0070] b) —CF₃,

[0071] c) —COR¹³,

[0072] d) —OR¹³,

[0073] e) —NR¹³R¹⁴

[0074] f) —NO₂,

[0075] g) —CN,

[0076] h) —SO₂OR¹³,

[0077] i) —Si(alkyl)₃, wherein each alkyl is independently selected,

[0078] j) —Si(aryl)₃, wherein each alkyl is independently selected,

[0079] k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,

[0080] l) —CO₂R¹³,

[0081] m) —C(O)NR¹³R¹⁴,

[0082] n) —SO₂NR¹³R¹⁴,

[0083] o) —SO₂R¹³,

[0084] p) —OC(O)R¹³,

[0085] q) —OC(O)NR¹³R¹⁴,

[0086] r) —NR¹³C(O)R¹⁴, and

[0087] s) —NR¹³CO₂R¹⁴;

[0088] (fluoroalkyl is one non-limiting example of an alkyl group thatis substituted with halogen);

[0089] R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

[0090] each R⁹ is independently selected from the group consisting of:

[0091] a) —R¹³,

[0092] b) halogen,

[0093] c) —CF₃,

[0094] d) —COR¹³,

[0095] e) —OR¹³,

[0096] f) —NR¹³R¹⁴

[0097] g) —NO₂,

[0098] h) —CN,

[0099] i) —SO₂R¹³,

[0100] j) —SO₂NR¹³R¹⁴,

[0101] k) —NR¹³COR¹⁴,

[0102] l) —CONR¹³R¹⁴

[0103] m) —NR¹³CO₂R¹⁴,

[0104] n) —CO₂R¹³,

[0105] p) alkyl substituted with one or more (e.g., one) —OH groups(e.g., —(CH₂)_(q)OH, wherein q is 1-6, usually 1 to 2, and preferably1),

[0106] q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group(e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1-6, usually 1 to 2, andpreferably 1), and

[0107] r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such asmethyl);

[0108] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of R¹³, hydrogen, alkyl (e.g., C₁ to C₆, such as methyl),halogen, —CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

[0109] R¹² is selected from the group consisting of: hydrogen,—C(O)OR¹³, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted arylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstitutedor substituted heteroarylalkyl group; wherein there are 1 to 6substituents on the substituted R¹² groups and each substituent isindependently selected from the group consisting of: R⁹ groups;

[0110] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or

[0111] R¹³ and R¹⁴ taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedheterocyclic ring), said ring optionally containing one additionalheteroatom selected from the group consisting of: O, S and NR¹⁸; whereinthere are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴groups (i.e., there is 1 to 3 substituents on the ring formed when theR¹³ and R¹⁴ groups are taken together with the nitrogen to which theyare bound) and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶,—NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group (i.e., aheterocyclic group that has at least one, and preferably one, doublebond in a ring, e.g.,

[0112] each R¹⁵ and R¹⁶ is independently selected from the groupconsisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0113] R¹⁷ is selected from the group consisting of: —SO₂alkyl,—SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl;

[0114] R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

[0115] each R¹⁹ and R²⁰ is independently selected from the groupconsisting of: alkyl, aryl and heteroaryl;

[0116] R³⁰ is selected from the group consisting of: alkyl, cycloalkyl,—CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

[0117] each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen and —CF₃;

[0118] each R⁴⁰ is independently selected from the group consisting of:H, alkyl and cycloalkyl; and

[0119] t is 0, 1 or 2.

[0120] An embodiment of the present invention is directed to a method oftreating a chemokine mediated disease in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0121] Examples of chemokine mediated diseases include: acuteinflammation, chronic inflammation, rheumatoid arthritis, acuteinflammatory pain, chronic inflammatory pain, acute neuropathic pain,chronic neuropathic pain, psoriasis, atopic dermatitis, asthma, COPD,adult respiratory disease, arthritis, inflammatory bowel disease,Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, cardiac and renalreperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease,graft vs. host reaction, allograft rejections, malaria, acuterespiratory distress syndrome, delayed type hypersensitivity reaction,atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiplesclerosis, restinosis, angiogenesis, osteoporosis, gingivitis,respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi'ssarcoma associated virus, meningitis, cystic fibrosis, pre-term labor,cough, pruritis, multi-organ dysfunction, trauma, strains, sprains,contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis,traumatic brain injury, CNS tumors, subarachnoid hemorrhage, postsurgical trauma, interstitial pneumonitis, hypersensitivity, crystalinduced arthritis, acute and chronic pancreatitis, acute alcoholichepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenicocular disease, ocular inflammation, retinopathy of prematurity,diabetic retinopathy, macular degeneration with the wet type preferredand corneal neovascularization, polymyositis, vasculitis, acne, gastricand duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis,bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough,dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia,hyperoxia-induced inflammations, hypoxia, surgical lung volumereduction, pulmonary fibrosis, pulmonary hypertension, right ventricularhypertrophy, peritonitis associated with continuous ambulatoryperitoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis,small airway disease, ventilation-perfusion mismatching, wheeze, colds,gout, alcoholic liver disease, lupus, bum therapy, periodontitis,transplant reperfusion injury and early transplantation rejection.

[0122] An embodiment of the present invention is directed to a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering to said patient,concurrently or sequentially, a therapeutically effective amount of (a)at least one (e.g., 1-3, and usually one) compound of formula IA, and(b) a microtubule affecting agent or antineoplastic agent oranti-angiogenesis agent or VEGF receptor kinase inhibitor or antibodiesagainst the VEGF receptor or interferon, and/or c) radiation.

[0123] In further embodiments directed to the treatment of cancer, atleast one (e.g., 1-3, and usually one) compound of formula IA isadministered in combination with antineoplastic agents (e.g., one ormore, such as one, or such as one or two), selected from the groupconsisting of: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU),cyclophosphamide (Cytoxan®), temozolomide, taxotere and Vincristine.

[0124] In another embodiment the present invention provides a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering, concurrently orsequentially, an effective amount of (a) a compound of formula IA, and(b) a microtubule affecting agent (e.g., paclitaxel).

[0125] Another embodiment of the present invention is directed to amethod of treating acute inflammatory pain, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0126] Another embodiment of the present invention is directed to amethod of treating chronic inflammatory pain, in a patient in need ofsuch treatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0127] Another embodiment of the present invention is directed to amethod of treating acute neuropathic pain, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0128] Another embodiment of the present invention is directed to amethod of treating chronic neuropathic pain, in a patient in need ofsuch treatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0129] Another embodiment of the present invention is directed to amethod of treating COPD, in a patient in need of such treatment (e.g., amammal, preferably a human being) comprising administering to saidpatient a therapeutically effective amount of at least one (e.g., 1-3,and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

[0130] Another embodiment of the present invention is directed to amethod of treating acute inflammation, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0131] Another embodiment of the present invention is directed to amethod of treating chronic inflammation, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0132] Another embodiment of the present invention is directed to amethod of treating rheumatoid arthritis, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

[0133] In another embodiment of the methods of this invention B isselected from the group consisting of:

[0134] wherein all substituents are as defined for formula IA.

[0135] In another embodiment of the methods of this invention B is:

[0136] wherein:

[0137] R², R⁴, R⁵ and R⁶ are as defined for formula IA; and

[0138] R³ is selected from the group consisting of: hydrogen, cyano,halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³,—C(O)NHR¹⁷, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR⁴, unsubstitutedor substituted aryl, unsubstituted or substituted heteroaryl, whereinthere are 1 to 6 substituents on said substituted aryl group and eachsubstituent is independently selected from the group consisting of: R⁹groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups.

[0139] In the methods of this invention:

[0140] (1) substituent A in formula IA is preferably selected from thegroup consisting of:

[0141] wherein the above rings are unsubstituted or substituted, asdescribed for formula IA: and

[0142] wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR ¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

[0143] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0144] wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above.

[0145] In the methods of this invention:

[0146] (1) substituent A in formula IA is more preferably selected fromthe group consisting of:

[0147] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected is from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹is selected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

[0148] wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0149] (2) substituent B in formula IA is more preferably selected fromthe group consisting of:

[0150] wherein

[0151] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ orand —NHSO₂R¹³;

[0152] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂,cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

[0153] R⁴ is selected from the group consisting of: H, —NO₂, cyano,—CH₃, halogen, and —CF₃;

[0154] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano;

[0155] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0156] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of: hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴,—C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, andcyano;

[0157] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0158] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from the group consisting of: O, S orNR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl,aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹and R²⁰ is independently selected from the group consisting of: alkyl,aryl and heteroaryl; wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on thering formed when R¹³ and R¹⁴ are taken together with the nitrogen towhich they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0159] In the methods of this invention:

[0160] (1) substituent A in formula IA is even more preferably selectedfrom the group consisting of:

[0161] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

[0162] wherein R⁷ is selected from the group consisting of: H,fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the groupconsisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined forformula IA.

[0163] In the methods of this invention:

[0164] (1) substituent A in formula IA is still even more preferablyselected from the group consisting of:

[0165] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0166] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA.

[0167] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0168] wherein:

[0169] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0170] R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,—SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

[0171] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0172] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0173] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0174] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0175] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0176] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from O, S or NR¹⁸ wherein R¹⁸ isselected from H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰ is independently selected fromalkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., on the ring formed whenR¹³ and R¹⁴ are taken together with the nitrogen to which they arebound) and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ andhalogen; and wherein each R¹⁵ and R¹⁶ is independently selected from thegroup consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl andheteroaryl.

[0177] In the methods of this invention:

[0178] (1) substituent A in formula IA is yet even still more preferablyselected from the group consisting of:

[0179] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0180] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA.

[0181] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0182] wherein:

[0183] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0184] R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³;

[0185] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0186] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0187] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0188] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0189] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: methyl and ethyl.

[0190] In the methods of this invention:

[0191] (1) substituent A in formula IA is most preferably selected fromthe group consisting of:

[0192] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0193] wherein:

[0194] R² is—OH;

[0195] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and—CONR¹³R¹⁴;

[0196] R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

[0197] R⁵ is selected from the group consisting of: H and cyano;

[0198] R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

[0199] R¹¹ is H; and

[0200] R¹³ and R¹⁴ are methyl.

[0201] The novel compounds of this invention are compounds of formulaIA:

[0202] and their pharmaceutically acceptable salts (e.g., sodium orcalcium salt) and solvates thereof, wherein:

[0203] A is selected from the group consisting of:

[0204] wherein the above rings of said A groups are substituted with 1to 6 substituents each independently selected from the group consistingof: R⁹ groups;

[0205] wherein one or both of the above rings of said A groups aresubstituted with 1 to 6 substituents each independently selected fromthe group consisting of: R⁹ groups;

[0206] wherein the above phenyl rings of said A groups are substitutedwith 1 to 3 substituents each independently selected from the groupconsisting of: R⁹ groups; and

[0207] B is selected from the group consisting of:

[0208] provided that R³ for this group is selected from the groupconsisting of: —C(O)NR¹³R¹⁴,

[0209] n is 0 to 6;

[0210] p is 1 to 5;

[0211] X is O, NH, or S;

[0212] Z is 1 to 3;

[0213] R² is selected from the group consisting of: hydrogen, OH,—C(O)OH, —SH, —SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³,an unsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

[0214] each R³ and R⁴ is independently selected from the groupconsisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴,—SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl,

[0215] wherein there are 1 to 6 substituents on said substituted arylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups; and wherein there are 1 to 6 substituents onsaid substituted heteroaryl group and each substituent is independentlyselected from the group consisting of: R⁹ groups;

[0216] each R⁵ and R⁶ are the same or different and are independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkoxy,—CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR ¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³R¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

[0217] each R⁷ and R⁸ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstituent is independently selected from the group consisting of:

[0218] a) halogen,

[0219] b) —CF₃,

[0220] c) —COR¹³,

[0221] d) —OR¹³,

[0222] e) —NR¹³R¹⁴

[0223] f) —NO₂,

[0224] g) —CN,

[0225] h) —SO₂R¹³,

[0226] i) —Si(alkyl)₃, wherein each alkyl is independently selected,

[0227] j) —Si(aryl)₃, wherein each alkyl is independently selected,

[0228] k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,

[0229] l) —CO₂R¹³,

[0230] m) —C(O)NR¹³R¹⁴,

[0231] n) —SO₂NR¹³R¹⁴,

[0232] o) —SO₂R¹³,

[0233] p) —OC(O)R¹³,

[0234] q) —OC(O)NR¹³R¹⁴

[0235] r) —NR¹³C(O)R¹⁴, and

[0236] s) —NR¹³CO₂R¹⁴;

[0237] (fluoroalkyl is one non-limiting example of an alkyl group thatis substituted with halogen);

[0238] R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

[0239] each R⁹ is independently selected from the group consisting of:

[0240] a) —R¹³,

[0241] b) halogen,

[0242] c) —CF₃,

[0243] d) —COR¹³,

[0244] e) —OR¹³,

[0245] f) —NR¹³R¹⁴

[0246] g) —NO₂,

[0247] h) —CN,

[0248] i) —SO₂R¹³,

[0249] j) —SO₂NR¹³R¹⁴,

[0250] k) —NR¹³COR¹⁴

[0251] l) —CONR¹³R¹⁴

[0252] m) —NR¹³CO₂R¹⁴,

[0253] n) —CO₂R¹³,

[0254] p) alkyl substituted with one or more (e.g., one) —OH groups(e.g., —(CH₂)_(q)OH, wherein q is 1-6, usually 1 to 2, and preferably1),

[0255] q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group(e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1-6, usually 1 to 2, andpreferably 1), and

[0256] r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such asmethyl);

[0257] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of R¹³, hydrogen, alkyl (e.g., C₁ to C₆, such as methyl),halogen, —CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

[0258] R¹² is selected from the group consisting of: hydrogen,—C(O)OR¹³, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted arylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstitutedor substituted heteroarylalkyl group; wherein there are 1 to 6substituents on the substituted R¹² groups and each substituent isindependently selected from the group consisting of: R⁹ groups;

[0259] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or

[0260] R¹³ and R¹⁴ taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedheterocyclic ring), said ring optionally containing one additionalheteroatom selected from the group consisting of: O, S and NR¹⁸; whereinthere are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴groups (i.e., there is 1 to 3 substituents on the ring formed when theR¹³ and R¹⁴ groups are taken together with the nitrogen to which theyare bound) and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶,—NHC(O)OR¹⁵, halogen, and a heterocylcoalkenyl group (i.e., aheterocyclic group that has at least one, and preferably one, doublebond in a ring, e.g.,

[0261] each R¹⁵ and R¹⁶ is independently selected from the groupconsisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0262] R¹⁷ is selected from the group consisting of: —SO₂alkyl,—SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl;

[0263] R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

[0264] each R¹⁹ and R²⁰ is independently selected from the groupconsisting of: alkyl, aryl and heteroaryl;

[0265] R³⁰ is selected from the group consisting of: alkyl, cycloalkyl,—CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

[0266] each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen, and —CF₃;

[0267] each R⁴⁰ is independently selected from the group consisting of:H, alkyl and cycloalkyl; and

[0268] t is 0, 1 or 2.

[0269] Representative embodiments of the novel compounds of thisinvention are described below. The embodiments have been numbered forpurposes of reference thereto.

[0270] Embodiment No. 1 is directed to the novel compounds of formula IAwherein B is selected from the group consisting of:

[0271] provided that R³ for this group is selected from the groupconsisting of: —C(O)NR¹³R¹⁴,

[0272] wherein all substituents are as defined for the novel compoundsof formula IA.

[0273] Embodiment No. 2 is directed to the novel compounds of formula IAwherein B is:

[0274] wherein R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴,

[0275] and all other substituents are as defined in formula IA.

[0276] Embodiment No. 3 is directed to the novel compounds of formula IAwherein B is:

[0277] and all other substituents are as defined in formula IA.

[0278] Embodiment No. 4 is directed to the novel compounds of formula IAwherein B is

[0279] R¹³ and R¹⁴ are each the same or different alkyl group, and allother substituents are as defined in formula IA .

[0280] Embodiment No. 5 is directed to the novel compounds of formula IAwherein B is

[0281] and (1) R² is —OH, and all other substituents are as defined informula IA, or (2) R² is —OH, and R¹³ and R¹⁴ are each the same ordifferent alkyl group, and all other substituents are as defined informula IA.

[0282] Embodiment No. 6 is directed to the novel compounds of formula IAwherein B is

[0283] R³ is selected from the group consisting of:

[0284] and all other substituents are as defined in formula IA.

[0285] Embodiment No. 7 is directed to the novel compounds of formula IAwherein B is

[0286] R³ is selected from the group consisting of:

[0287] R² is —OH, and all other substituents are as defined in formulaIA.

[0288] Embodiment No. 8 is directed to compounds of formula IA wherein Bis:

[0289] R², R¹³, and R¹⁴ are as defined for compounds of formula IA, andall other substituents are as defined in formula IA.

[0290] Embodiment No. 9 is directed to the novel compounds of formula IAwherein B is:

[0291] R² is —OH, R¹³ and R¹⁴ are as defined for compounds of formulaand all other substituents are as defined in formula IA.

[0292] Embodiment No. 10 is directed to the novel compounds of formulaIA wherein B is:

[0293] R² is as defined for compounds of formula IA, R¹³ and R¹⁴ are thesame or different alkyl group, and all other substituents areas definedfor compounds of formula IA.

[0294] Embodiment No. 11 is directed to the novel compounds of formulaIA wherein B is:

[0295] R² is —OH, R¹³ and R¹⁴ are the same or different alkyl group, andall other substituents areas defined for compounds of formula IA.

[0296] Embodiment No. 12 is directed to novel compounds of formula IAwherein B is as described in Embodiment No. 6, R⁴ is H, R⁵ is H, R⁶ isH, and all other substituents areas defined for compounds of formula IA.

[0297] Embodiment No. 13 is directed to novel compounds of formula IAwherein B is as described in Embodiment No. 7, R⁴ is H, R⁵ is H, R⁶ isH, and all other substituents areas defined for compounds of formula IA.

[0298] Embodiment No. 14 is directed to novel compounds of formula IAwherein B is as described in Embodiments Nos. 4, 5, 8 and 9, except thatR¹³ and R¹⁴ are each methyl, and all other substituents are as definedin formula IA.

[0299] Embodiment No. 15 is directed to novel compounds of formula IAwherein B is selected from the group consisting of:

[0300] wherein all substituents are as defined for formula IA.

[0301] Embodiment No. 16 is directed to compounds of formula IA whereinB is:

[0302] wherein all substituents are as defined for formula IA.

[0303] Embodiment No. 17 is directed to compounds of formula IA whereinB is:

[0304] R¹¹ is H, and all other substituents are as defined in formulaIA.

[0305] Embodiment No. 18 is directed to compounds of formula IA whereinB is:

[0306] R² is —OH, and all other substituents are as defined in formulaIA.

[0307] Embodiment No. 19 is directed to compounds of formula IA whereinB is:

[0308] R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined informula IA.

[0309] Embodiment No. 20 is directed to compounds of formula IA whereinB is:

[0310] R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituentsare as defined in formula IA.

[0311] Embodiment No. 21 is directed to compounds of formula IA whereinB is:

[0312] R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are asdefined in formula IA.

[0313] Embodiment No. 22 of this invention is directed to compounds offormula IA wherein B is:

[0314] R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and allother substituents are as defined in formula IA.

[0315] Embodiment No. 23 is directed to compounds of formula IA whereinB is:

[0316] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all othersubstituents are as defined in formula IA.

[0317] Embodiment No. 24 is directed to compounds of formula IA whereinB is:

[0318] R³ is —S(O_(t)NR¹³R¹⁴ (e.g., t is 2), each R¹³ and R¹⁴ are thesame or different and are selected from the group consisting of: H andalkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment,each R¹³ and R¹⁴ are generally selected from the group consisting of: Hand ethyl, and preferably R¹³ and R¹⁴ are ethyl.and all othersubstituents are as defined in formula IA.

[0319] Embodiment No. 25 is directed to compounds of formula IA whereinB is:

[0320] R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and each R¹³ andR¹⁴ are the same or different and are selected from the group consistingof: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In thisembodiment, each R¹³ and R¹⁴ are generally selected from the groupconsisting of: H and ethyl, and preferably R¹³ and R¹⁴ are ethyl.and allother substituents are as defined in formula IA.

[0321] Embodiment No. 26 is directed to compounds of formula IA whereinB is:

[0322] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, andall other substituents are as defined in formula IA.

[0323] Embodiment No. 27 is directed to compounds of formula LA whereinB is:

[0324] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ areindependently selected from the group consisting of: alkyl,unsubstituted heteroaryl and substituted heteroaryl, and all othersubstituents are as defined in formula IA. In general, one of R¹³ or R¹⁴is alkyl (e.g., methyl). An example of a substituted heteroaryl group is

[0325] Embodiment No. 28 is directed to compounds of formula IA whereinB is:

[0326] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, andeach R¹³ and R¹⁴ are the same or different and are selected from thegroup consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl andt-butyl), and all other substituents are as defined in formula IA. Inthis embodiment, each R¹³ and R¹⁴ are generally selected from the groupconsisting of: H and ethyl, and preferably R¹³ and R¹⁴ are ethyl.

[0327] Embodiment No. 29 is directed to compounds of formula IA whereinB is:

[0328] and all substituents are as defined in formula IA.

[0329] Embodiment No. 30 is directed to compounds of formula IA whereinB is:

[0330] and all substituents are as defined in formula IA.

[0331] Embodiment No. 31 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is as defined in any of the above preferred descriptions describing Afor the compounds of formula IA used in the methods of treatment.

[0332] Embodiment No. 32 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is:

[0333] wherein the furan ring is unsubstituted or substituted asdescribed in the definition of A for formula IA, and all othersubstituents are as defined for formula IA.

[0334] Embodiment No. 33 is directed to novel compounds of formula IAwherein B is described in any one of the Embodiment Nos. 1 to 30, and Ais

[0335] wherein the furan ring is substituted and all other substituentsare as defined for formula IA.

[0336] Embodiment No. 34 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is

[0337] wherein the furan ring is substituted with at least one (e.g., 1to 3, or 1 to 2) alkyl group and all other substituents are as definedfor formula IA.

[0338] Embodiment No. 35 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, Ais

[0339] wherein the furan ring is substituted with one alkyl group andall other substituents are as defined for formula IA.

[0340] Embodiment No. 36 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is

[0341] wherein the furan ring is substituted with one C, to C₃ alkylgroup (e.g., methyl or isopropyl), and all other substituents are asdefined for formula IA.

[0342] Embodiment No. 37 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is

[0343] as defined in any one of the Embodiment Nos. 32 to 36, exceptthat R⁷ and R⁸ are the same or different and each is selected from thegroup consisting of: H and alkyl.

[0344] Embodiment No. 38 is directed to novel compounds of formula IAwherein B is as described in any one of the Embodiment Nos. 1 to 30, andA is

[0345] as defined in any one of the Embodiment Nos. 32 to 36, exceptthat R⁷ is H, and R⁸ is alkyl (e.g., ethyl or t-butyl).

[0346] Embodiment No. 39 is directed to the novel compounds of formulaIA wherein:

[0347] (1) substituent A in formula IA is preferably selected from thegroup consisting of:

[0348] wherein the above rings are unsubstituted or substituted, asdescribed for formula IA: and

[0349] and wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

[0350] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0351] wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for thenovel compounds of formula IA.

[0352] Embodiment No. 40 is directed to the novel compounds of formulaIA wherein:

[0353] (1) substituent A in formula IA is more preferably selected fromthe group consisting of:

[0354] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

[0355] wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, is—OCH₃, and —NO₂; each R¹⁷and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0356] (2) substituent B in formula IA is more preferably selected fromthe group consisting of:

[0357] wherein

[0358] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0359] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂,cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

[0360] R⁴ is selected from the group consisting of: H, —NO₂, cyano,—CH₃, halogen, and —CF₃;

[0361] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano;

[0362] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0363] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of: R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴,—C(O)OR¹³, —SH, —SO_((t))NR¹³R ¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, andcyano;

[0364] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0365] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected fromthe group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selectedfrom the group consisting of: alkyl, aryl and heteroaryl; wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., the substituents on the ring formed when R¹³ and R¹⁴ are takentogether with the nitrogen to which they are bound) and each substituentis independently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0366] Embodiment No. 41 is directed to the novel compounds of formulaIA wherein:

[0367] substituent A in formula IA is even more preferably selected fromthe group consisting of:

[0368] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

[0369] wherein R⁷ is selected from the group consisting of: H,fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the groupconsisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined forformula IA.

[0370] Embodiment No. 42 is directed to the novel compounds of formulaIA wherein:

[0371] (1) substituent A in formula IA is still even more preferablyselected from the group consisting of:

[0372] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0373] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA.

[0374] (2) substituent B in formula IA is preferably selected from thegroup consisting of:

[0375] wherein:

[0376] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R ¹³;

[0377] R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,—SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

[0378] R⁴is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0379] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0380] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0381] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0382] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0383] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰is independently selected from alkyl, aryl and heteroaryl, wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., on the ring formed when R¹³ and R¹⁴ are taken together with thenitrogen to which they are bound) and each substituent is independentlyselected from the group consisting of: alkyl, aryl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H. alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0384] Embodiment No. 43 is directed to the novel compounds of formulaIA wherein:

[0385] (1) substituent A in formula IA is yet even still more preferablyselected from the group consisting of:

[0386] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0387] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA;

[0388] (2) substituent B in formula IA is yet even still more preferablyselected from the group consisting of:

[0389] wherein:

[0390] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0391] R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³;

[0392] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0393] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0394] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0395] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0396] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: methyl and ethyl.

[0397] Embodiment No. 44 is directed to the novel compounds of formulaIA wherein:

[0398] (1) substituent A in formula IA is most preferably selected fromthe group consisting of:

[0399] (2) substituent B in formula IA is most preferably selected fromthe group consisting of:

[0400] wherein:

[0401] R²is —OH;

[0402] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and—CONR¹³R¹⁴;

[0403] R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

[0404] R⁵ is selected from the group consisting of: H and cyano;

[0405] R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

[0406] R¹¹ is H; and

[0407] R¹³ and R¹⁴ are methyl.

[0408] Embodiment No. 45 is directed to the novel compounds of formulaIA wherein:

[0409] (1) substituent A in formula IA is selected from the groupconsisting of:

[0410] wherein the above rings are unsubstituted or substituted, asdescribed for formula IA: and

[0411] wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

[0412] (2) substituent B in formula IA is:

[0413] wherein R², R³ and R¹¹ are as defined above for the novelcompounds of formula IA.

[0414] Embodiment No. 46 is directed to the novel compounds of formulaIA wherein:

[0415] (1) substituent A in formula IA is selected from the groupconsisting of:

[0416] wherein the above rings are unsubstituted or substituted, asdescribed for formula IA: and

[0417] and

[0418] wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

[0419] (2) substituent B in formula IA is:

[0420] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0421] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂,cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

[0422] R¹¹ is selected from the group consisting of: R¹³, hydrogen,halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³ —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³—C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, andcyano;

[0423] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0424] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴, form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected fromthe group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selectedfrom the group consisting of: alkyl, aryl and heteroaryl; wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., the substituents on the ring formed when R¹³ and R¹⁴ are takentogether with the nitrogen to which they are bound) and each substituentis independently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0425] Embodiment No. 47 is directed to the novel compounds of formulaIA wherein:

[0426] (1) substituent A in formula IA is selected from the groupconsisting of:

[0427] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

[0428] wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0429] (2) substituent B in formula IA is:

[0430] wherein

[0431] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ orand —NHSO₂R¹³;

[0432] R³ is —SO₂NR¹³R¹⁴;

[0433] R¹¹ is selected from the group consisting of: R¹³, hydrogen,halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

[0434] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0435] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the group —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedring) optionally having one additional heteroatom selected from thegroup consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected from thegroup consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selected fromthe group consisting of: alkyl, aryl and heteroaryl; wherein there are 1to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e.,the substituents on the ring formed when R¹³ and R¹⁴ are taken togetherwith the nitrogen to which they are bound) and each substituent isindependently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0436] Embodiment No. 48 is directed to the novel compounds of formulaIA wherein:

[0437] (1) substituent A in formula IA is selected from the groupconsisting of:

[0438] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0439] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA.

[0440] (2) substituent B in formula IA is:

[0441] wherein:

[0442] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0443] R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,—SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

[0444] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0445] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl, isopropyl and t-butyl.

[0446] Embodiment No. 43 is directed to the novel compounds of formulaIA wherein:

[0447] (1) substituent A in formula IA is selected from the groupconsisting of:

[0448] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0449] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA;

[0450] (2) substituent B in formula IA is:

[0451] wherein:

[0452] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³ (preferably —OH);

[0453] R³ is —SO₂NR¹³R¹⁴;

[0454] R¹¹ is selected from the group consisting of: H, halogen andalkyl (preferably H); and

[0455] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H and ethyl, preferably R¹³ and R¹⁴ are ethyl.

[0456] Embodiment No. 50 is directed to the novel compounds of formulaIA wherein:

[0457] (1) substituent A in formula IA is selected from the groupconsisting of:

[0458] (2) substituent B in formula IA is:

[0459] wherein:

[0460] R² is —OH;

[0461] R³ is: —SO₂NR¹³R¹⁴;

[0462] R¹¹ is H; and

[0463] R¹³ and R¹⁴ are ethyl.

[0464] Embodiment No. 51 is directed to compounds of formula IA whereinB is selected from the group consisting of:

[0465] provided that R³ for this group is selected from the groupconsisting of: —C(O)NR¹³R¹⁴,

[0466] wherein all other substituents are as defined for formula IA.

[0467] Embodiment No. 52 is directed to compounds of formula IA whereinB is selected from the group consisting of:

[0468] wherein all substituents are as defined for formula IA.

[0469] Embodiment No. 53 is directed to compounds of formula IA whereinB is:

[0470] wherein all substituents are as defined for formula IA.

[0471] Embodiment No. 54 is directed to compounds of formula IA whereinB is:

[0472] wherein all substituents are as defined for formula IA.

[0473] Embodiment No. 55 is directed to compounds of formula IA whereinB is:

[0474] wherein all substituents are as defined for formula IA.

[0475] Embodiment No. 56 is directed to compounds of formula IA whereinB is:

[0476] wherein all substituents are as defined for formula IA.

[0477] Embodiment No. 57 is directed to compounds of formula IA whereinB is:

[0478] wherein all substituents are as defined for formula IA.

[0479] Embodiment No. 58 is directed to compounds of formula IA whereinB is:

[0480] wherein all substituents are as defined for formula IA.

[0481] Embodiment No. 59 is directed to compounds of formula IA whereinB is:

[0482] wherein all substituents are as defined for formula IA.

[0483] Embodiment No. 60 is directed to compounds of formula IA whereinB is:

[0484] wherein all substituents are as defined for formula IA.

[0485] Embodiment No. 61 is directed to compounds of formula IA whereinB is:

[0486] wherein all substituents are as defined for formula IA.

[0487] Embodiment No. 62 is directed to compounds of formula IA whereinB is selected from the group consisting of:

[0488] wherein all substituents are as defined for formula IA.

[0489] Embodiment No. 63 is directed to compounds of formula IA whereinB is described in any of Embodiment Nos. 51 to 62 and A is as describedin any of Embodiments Nos. 31-44.

[0490] Embodiment No. 64 is directed to any one of the Embodiment Nos. 1to 63 wherein the novel compound of formula IA is a pharmaceuticallyacceptable salt.

[0491] Embodiment No. 65 is directed to any one of the Embodiment Nos. 1to 63 wherein the novel compound of formula IA is a sodium salt.

[0492] Embodiment No. 66 is directed to any one of the Embodiment Nos. 1to 63 wherein the novel compound of formula IA is a calcium salt.

[0493] Embodiment No. 67 is directed to a pharmaceutically acceptablesalt of any one of the representative novel compounds described below.

[0494] Embodiment No. 68 is directed to a sodium salt of any one of therepresentative novel compounds described below.

[0495] Embodiment No. 69 is directed to a calcium salt of any one of therepresentative novel compounds described below.

[0496] Embodiment No. 70 is directed to a pharmaceutical compositioncomprising at least one (e.g., 1 to 3, usually 1) novel compound offormula IA as described in any one of the Embodiment Nos. 1 to 69 incombination with a pharmaceutically acceptable carrier (or diluent).

[0497] Embodiment No. 71 is directed to a method of treating any one ofthe diseases described herein (e.g., the chemokine mediated diseases,and cancer) comprising administering to a patient in need of suchtreatment an effective amount (e.g., a therapeutically effective amount)of a novel compound of formula IA as described in any one of theEmbodiment Nos. 1 to 69.

[0498] Embodiment No. 72 is directed to novel compounds of Examples2006, 2010, 2015, 2029, 2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079,and 2087.

[0499] Embodiment No. 73 is directed to a pharmaceutical compositioncomprising at least one (e.g., 1 to 3, usually 1) novel compound ofEmbodiment No. 72 (or a pharmaceutically acceptable salt or solvatethereof, e.g., a calcium or sodium salt) in combination with apharmaceutically acceptable carrier (or diluent).

[0500] Embodiment No. 74 is directed to a method of treating any one ofthe diseases described herein (e.g., the chemokine mediated diseases,and cancer) comprising administering to a patient in need of suchtreatment an effective amount (e.g., a therapeutically effective amount)of at least one (e.g., 1 to 3, usually 1) compound of

[0501] Embodiment No. 72 (or a pharmaceutically acceptable salt orsolvate thereof, e.g., a calcium or sodium salt).

[0502] Representative compounds of the invention include but are notlimited to:

[0503] Preferred compounds of the invention include:

[0504] A more preferred group of compounds includes:

[0505] A most preferred group of compounds includes:

[0506] Certain compounds of the invention may exist in differentstereoisomeric forms (e.g., enantiomers, diastereoisomers andatropisomers). The invention contemplates all such stereoisomers both inpure form and in admixture, including racemic mixtures. Isomers can beprepared using conventional methods.

[0507] Certain compounds will be acidic in nature, e.g. those compoundswhich possess a carboxyl or phenolic hydroxyl group. These compounds mayform pharmaceutically acceptable salts. Examples of such salts mayinclude sodium, potassium, calcium, aluminum, gold and silver salts.Also contemplated are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

[0508] Certain basic compounds also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the pyrido-nitrogen atomsmay form salts with strong acid, while compounds having basicsubstituents such as amino groups also form salts with weaker acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those skilled in the art. The saltsare prepared by contacting the free base form with a sufficient amountof the desired acid to produce a salt in the conventional manner. Thefree base forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

[0509] All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

[0510] Compounds of formula IA can exist in unsolvated and solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for the purposes of thisinvention.

[0511] In a preferred embodiment of the treatment of cancer, a compoundof formula IA is administered in combination with one of the followingantineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorourcil(5-FU), cyclophosphamide (Cytoxan®), temozolomide, or Vincristine.

[0512] In another preferred embodiment, the present invention provides amethod of treating cancer, comprising administering, concurrently orsequentially, and effective amount of a compound of formula IA and amicrotubule affecting agent e.g., paclitaxel.

[0513] Another embodiment of the invention is directed to a methodtreating cancer, comprising administering to a patient in need thereof,concurrently or sequentially, a therapeutically effective amount of (a)a compound of formula IA, and (b) an antineoplastic agent, microtubuleaffecting agent or anti-angiogenesis agent.

[0514] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

[0515] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0516] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0517] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0518] The compounds of the invention may also be deliverabletransdermally. The transdermal composition can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0519] Preferably the compound is administered orally.

[0520] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0521] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.01 mg to about 1000 mg, preferablyfrom about 0.01 mg to about 750 mg, more preferably from about 0.01 mgto about 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular application.

[0522] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldosage may be divided and administered in portions during the day asrequired.

[0523] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses.

[0524] Classes of compounds that can be used as the chemotherapeuticagent (antineoplastic agent) include: alkylating agents,antimetabolites, natural products and their derivatives, hormones andsteroids (including synthetic analogs), and synthetics. Examples ofcompounds within these classes are given below.

[0525] Alkylating agents (including nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracilmustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

[0526] Antimetabolites (including folic acid antagonists, pyrimidineanalogs, purine analogs and adenosine deaminase inhibitors):Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

[0527] Natural products and their derivatives (including vincaalkaloids, antitumor antibiotics, enzymes, lymphokines andepipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,paclitaxel (paclitaxel is commercially available as Taxol® and isdescribed in more detail below in the subsection entitled “MicrotubuleAffecting Agents”), Mithramycin, Deoxyco-formycin, Mitomycin-C,L-Asparaginase, Interferons (especially IFN-a), Etoposide, andTeniposide.

[0528] Hormones and steroids (including synthetic analogs):17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex.

[0529] Synthetics (including inorganic complexes such as platinumcoordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, andHexamethylmelamine.

[0530] Methods for the safe and effective administration of most ofthese chemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 2002edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); thedisclosure of which is incorporated herein by reference thereto.

[0531] As used herein, a microtubule affecting agent is a compound thatinterferes with cellular mitosis, i.e., having an anti-mitotic effect,by affecting microtubule formation and/or action. Such agents can be,for instance, microtubule stabilizing agents or agents that disruptmicrotubule formation.

[0532] Microtubule affecting agents useful in the invention are wellknown to those of skill in the art and include, but are not limited toallocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine(NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel(Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),epothilone A, epothilone, and discodermolide (see Service, (1996)Science, 274:2009) estramustine, nocodazole, MAP4, and the like.Examples of such agents are also described in the scientific and patentliterature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda(1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) CancerRes. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997)Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.

[0533] Particularly preferred agents are compounds with paclitaxel-likeactivity. These include, but are not limited to paclitaxel andpaclitaxel derivatives (paclitaxel-like compounds) and analogues.Paclitaxel and its derivatives are available commercially. In addition,methods of making paclitaxel and paclitaxel derivatives and analoguesare well known to those of skill in the art (see, e.g., U.S. Pat. Nos.5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589;5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769;5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

[0534] More specifically, the term “paclitaxel” as used herein refers tothe drug commercially available as Taxol® (NSC number: 125973). Taxol®inhibits eukaryotic cell replication by enhancing polymerization oftubulin moieties into stabilized microtubule bundles that are unable toreorganize into the proper structures for mitosis. Of the many availablechemotherapeutic drugs, paclitaxel has generated interest because of itsefficacy in clinical trials against drug-refractory tumors, includingovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23,Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J.Natl. Canc. Inst. 82:1247-1259).

[0535] Additional microtubule affecting agents can be assessed using oneof many such assays known in the art, e.g., a semiautomated assay whichmeasures the tubulin-polymerizing activity of paclitaxel analogs incombination with a cellular assay to measure the potential of thesecompounds to block cells in mitosis (see Lopes (1997) Cancer Chemother.Pharmacol. 41:3747).

[0536] Generally, activity of a test compound is determined bycontacting a cell with that compound and determining whether or not thecell cycle is disrupted, in particular, through the inhibition of amitotic event. Such inhibition may be mediated by disruption of themitotic apparatus, e.g., disruption of normal spindle formation. Cellsin which mitosis is interrupted may be characterized by alteredmorphology (e.g., microtubule compaction, increased chromosome number,etc.).

[0537] Compounds with possible tubulin polymerization activity can bescreened in vitro. In a preferred embodiment, the compounds are screenedagainst cultured WR21 cells (derived from line 69-2 wap-ras mice) forinhibition of proliferation and/or for altered cellular morphology, inparticular for microtubule compaction. In vivo screening ofpositive-testing compounds can then be performed using nude mice bearingthe WR21 tumor cells. Detailed protocols for this screening method aredescribed by Porter (1995) Lab. Anim. Sci., 45(2):145-150.

[0538] Other methods of screening compounds for desired activity arewell known to those of skill in the art. Typically such assays involveassays for inhibition of microtubule assembly and/or disassembly. Assaysfor microtubule assembly are described, for example, by Gaskin et al.(1974) J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 alsoprovides in vitro and in vivo assays for compounds with paclitaxel-likeactivity.

[0539] Methods for the safe and effective administration of theabove-mentioned microtubule affecting agents are known to those skilledin the art. In addition, their administration is described in thestandard literature. For example, the administration of many of thechemotherapeutic agents is described in the “Physicians' Desk Reference”(PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J.07645-1742, USA); the disclosure of which is incorporated herein byreference thereto.

[0540] The amount and frequency of administration of the compounds offormula IA and the chemotherapeutic agents and/or radiation therapy willbe regulated according to the judgment of the attending clinician(physician) considering such factors as age, condition and size of thepatient as well as severity of the disease being treated. A dosageregimen of the compound of formula IA can be oral administration of from10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50to 600 mg/day, in two to four (preferably two) divided doses, to blocktumor growth. Intermittant therapy (e.g., one week out of three weeks orthree out of four weeks) may also be used.

[0541] The chemotherapeutic agent and/or radiation therapy can beadministered according to therapeutic protocols well known in the art.It will be apparent to those skilled in the art that the administrationof the chemotherapeutic agent and/or radiation therapy can be varieddepending on the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

[0542] In the methods of this invention, a compound of formula IA isadministered concurrently or sequentially with a chemotherapeutic agentand/or radiation. Thus, it is not necessary that, for example, thechemotherapeutic agent and the compound of formula IA, or the radiationand the compound of formula IA, should be administered simultaneously oressentially simultaneously. The advantage of a simultaneous oressentially simultaneous administration is well within the determinationof the skilled clinician.

[0543] Also, in general, the compound of formula IA and thechemotherapeutic agent do not have to be administered in the samepharmaceutical composition, and may, because of different physical andchemical characteristics, have to be administered by different routes.For example, the compound of formula IA may be administered orally togenerate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician .

[0544] The particular choice of a compound of formula IA, andchemotherapeutic agent and/or radiation will depend upon the diagnosisof the attending physicians and their judgement of the condition of thepatient and the appropriate treatment protocol.

[0545] The compound of formula IA, and chemotherapeutic agent and/orradiation may be administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol) orsequentially, depending upon the nature of the proliferative disease,the condition of the patient, and the actual choice of chemotherapeuticagent and/or radiation to be administered in conjunction (i.e., within asingle treatment protocol) with the compound of formula or IA.

[0546] If the compound of formula IA, and the chemotherapeutic agentand/or radiation are not administered simultaneously or essentiallysimultaneously, then the initial order of administration of the compoundof formula IA, and the chemotherapeutic agent and/or radiation, may notbe important. Thus, the compound of formula IA may be administeredfirst, followed by the administration of the chemotherapeutic agentand/or radiation; or the chemotherapeutic agent and/or radiation may beadministered first, followed by the administration of the compound offormula IA. This alternate administration may be repeated during asingle treatment protocol. The determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is well within theknowledge of the skilled physician after evaluation of the disease beingtreated and the condition of the patient.

[0547] For example, the chemotherapeutic agent and/or radiation may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compound of formulaIA followed, where determined advantageous, by the administration of thechemotherapeutic agent and/or radiation, and so on until the treatmentprotocol is complete.

[0548] Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent—i.e., the compound of formula IA, chemotherapeuticagent or radiation) of the treatment according to the individualpatient's needs, as the treatment proceeds.

[0549] The attending clinician, in judging whether treatment iseffective at the dosage administered, will consider the generalwell-being of the patient as well as more definite signs such as reliefof disease-related symptoms, inhibition of tumor growth, actualshrinkage of the tumor, or inhibition of metastasis. Size of the tumorcan be measured by standard methods such as radio-logical studies, e.g.,CAT or MRI scan, and successive measurements can be used to judgewhether or not growth of the tumor has been retarded or even reversed.Relief of disease-related symptoms such as pain, and improvement inoverall condition can also be used to help judge effectiveness oftreatment.

BIOLOGICAL EXAMPLES

[0550] The compounds of the present invention are useful in thetreatment of CXC-chemokine mediated conditions and diseases. Thisutility is manifested in their ability to inhibit IL-8 and GRO-αchemokine as demonstrated by the following in vitro assays.

[0551] Receptor Binding Assays:

[0552] CXCR1 SPA Assay

[0553] For each well of a 96 well plate, a reaction mixture of 10 μghCXCR1-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPAbeads (Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mMHEPES, pH 7.8, 2 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl, 0.1% BSA) (Sigma). A0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1assay buffer. 20× stock solutions of test compounds were prepared inDMSO (Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2assay buffer. The above solutions were added to a 96-well assay plate(PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assaybuffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock(Final [Ligand]=0.1 nM). The assay plates were shaken for 5 minutes onplate shaker, then incubated for 8 hours before cpm/well were determinedin Microbeta Trilux counter (PerkinElmer). % Inhibition of Totalbinding-NSB (250 nM IL-8) was determined for IC50 values. Compounds ofthis invention had an IC₅₀ of <20 μM. The most preferred compounds had aK_(i) within the range of 3 nM to 1120 nM.

[0554] CXCR2 SPA Assay

[0555] For each well of a 96 well plate, a reaction mixture of 4 μghCXCR2-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPAbeads (Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mMHEPES, pH 7.4, 2 mM CaCl₂, 1 mM MgCl₂). A 0.4 nM stock of ligand,[125I]-IL-8 (NEN), was prepared in the CXCR2 assay buffer. 20× stocksolutions of test compounds were prepared in DMSO (Sigma). A 6× stocksolution of GRO-α (R&D) was prepared in CXCR2 assay buffer. The abovesolutions were added to a 96-well assay plate (PerkinElmer or Corning)as follows: 10 μl test compound or DMSO, 40 ul CXCR2 assay buffer orGRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final[Ligand]=0.1 nM). When 40× stock solutions of test compounds in DMSOwere prepared, then the above protocol was used except instead 5 μl testcompound or DMSO and 45 μl CXCR2 assay buffer were used. The assayplates were shaken for 5 minutes on a plate shaker, then incubated for2-8 hours before cpm/well were determined in Microbeta Trilux counter(PerkinElmer). % Inhibition of total binding minus non-specific binding(250 nM Gro-α or 50 μM antagonist) was determined and IC50 valuescalculated. Compounds of this invention had an IC₅₀ of <5 μM. The mostpreferred compounds had a K_(i) within the range of 0.8 nM to 40 nM. Thecompound of Example 360.31 had a K_(i) of 3 nM. The compound of Example360.106 had a K_(i) of 0.8 nM.

[0556] Calcium Fluorescence Assay (FLIPR)

[0557] HEK 293 cells stably transfected with hCXCR2 and Gαι/q wereplated at 10,000 cells per well in a Poly-D-Lysine Black/Clear plate(Becton Dickinson) and incubated 48 hours at 5% CO₂, 37° C. The cultureswere then incubated with 4 mM fluo-4, AM (Molecular Probes) in DyeLoading Buffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mMProbenicid (Sigma) for 1 hour. The cultures were washed with wash buffer(HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then100 μl/well wash buffer was added.

[0558] During incubation, compounds were prepared as 4× stocks in 0.4%DMSO (Sigma) and wash buffer and added to their respective wells in thefirst addition plate. IL-8 or GRO-α (R&D Systems) concentrations wereprepared 4× in wash buffer+0.1% BSA and added to their respective wellsin second addition plate.

[0559] Culture plate and both addition plates were then placed in theFLIPR imaging system to determine change in calcium fluorescence uponaddition of compound and then ligand. Briefly, 50 μl of compoundsolutions or DMSO solution was added to respective wells and change incalcium fluorescence measured by the FLIPR for 1 minute. After a 3minute incubation within the instrument, 50 μl of ligand was then addedand the change in calcium fluorescence measured by the FLIPR instrumentfor 1 minute. The area under each stimulation curve was determined andvalues used to determine % Stimulation by compound (agonist) and %Inhibition of Total Calcium response to ligand (0.3 nM IL-8 or GRO-α)for IC50 values of the test compounds.

[0560] Chemotaxis Assays for 293-CXCR2

[0561] A chemotaxis assay is setup using Fluorblok inserts (Falcon) for293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standardprotocol used at present is as follows:

[0562] 1. Inserts are coated with collagenIV (2 ug/ml) for 2 hrs at 37°C.

[0563] 2. The collagen is removed and inserts are allowed to air dryovernight.

[0564] 3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for2 hrs. Labeling is done in complete media with 2% FBS.

[0565] 4. Dilutions of compound are made in minimal media (0.1% BSA) andplaced inside the insert which is positioned inside the well of a 24well plate. Within the well is IL-8 at a concentration of 0.25 nM inminimal media. Cells are washed and resuspended in minimal media andplaced inside the insert at a concentration of 50,000 cells per insert.

[0566] 5. Plate is incubated for 2 hrs and inserts are removed andplaced in a new 24 well. Fluorescence is detected at excitation=485 nMand emission=530 nM.

[0567] Cytotoxicity Assays

[0568] A cytotoxicity assay for CXCR2 compounds is conducted on293-CXCR2 cells. Concentrations of compounds are tested for toxicity athigh concentrations to determine if they may be used for furtherevaluation in binding and cell based assays. The protocol is as follows:

[0569] 1. 293-CXCR2 cells are plated overnight at a concentration of5000 cells per well in complete media.

[0570] 2. Dilutions of compound are made in minimal media w/0.1% BSA.Complete media is poured off and the dilutions of compound are added.Plates are incubated for 4, 24 and 48 hrs. Cells are labeled with 10 uMcalcein AM for 15 minutes to determine cell viability. Detection methodis the same as above.

[0571] Soft Agar Assay

[0572] 10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agarand complete media with various dilutions of compound. Finalconcentration of agar is 0.6%. After 21 days viable cell colonies arestained with a solution of MTT (1 mg/ml in PBS). Plates are then scannedto determine colony number and size. IC₅₀ is determined by comparingtotal area vs. compound concentration.

[0573] Compounds of formula IA may be produced by processes known tothose skilled in the art, in the following reaction schemes, and in thepreparations and examples below.

[0574] A general procedure for the preparation of compounds of formulaIA is as follows:

[0575] Scheme 1

[0576] An amine is condensed (Step A) with a nitrosalicylic acid understandard coupling conditions and the resulting nitrobenzamide is reduced(Step B) under hydrogen atmosphere in the presence of a suitablecatalyst. The remaining partner required for the synthesis of the finaltarget is prepared by condensing an aryl amine with the commerciallyavailable diethylsquarate to give the aminoethoxysquarate product.Subsequent condensation of this intermediate with the aminobenzamideprepared earlier provides the desired chemokine antagonist (Scheme 1).

[0577] Scheme 2

[0578] Alternatively, the aminobenzamide of Scheme 1 is first condensedwith commercially available diethylsquarate to give an alternatemonoethoxy intermediate. Condensation of this intermediate with an aminegives the desired chemokine antagonist.

[0579] Scheme 3

[0580] Benztriazole compounds of Formula (I) or IA are prepared bystirring nitrophenylenediamines with sodium nitrite in acetic acid at60° C. to afford the nitrobenzotriazole intermediate (Scheme 3).Reduction of the nitro group in the presence of palladium catalyst andhydrogen atmosphere provides the amine compound. Subsequent condensationof this intermediate with the aminooethoxysquarate prepared earlier(Scheme 1) provides the desired chemokine antagonist.

[0581] Scheme 4

[0582] Condensation of nitrophenylenediamines with anhydrides oractivated acids at reflux (Scheme 4) affords benzimidazole intermediateswhich after reduction with hydrogen gas and palladium catalyst andcondensation with the aminoethoxysquarate previously prepared (Scheme 1)affords benzimidazole chemokine antagonists.

[0583] Scheme 5

[0584] Indazole structures of Formula (I) or IA can be preparedaccording to Scheme 5 by reduction of nitroindazole A (J. Am. Chem Soc.1943, 65, 1804-1805) to give aminoindazole B and subsequent condensationwith the aminoethoxysquarate prepared earlier (Scheme 1).

[0585] Scheme 6

[0586] Indole structures of Formula (I) or IA can be prepared accordingto Scheme 6 by reduction of nitroindole A (J. Med. Chem. 1995, 38,1942-1954) to give aminoindole B and subsequent condensation with theaminoethoxysquarate prepared earlier (Scheme 1).

[0587] The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

Preparative Example 1

[0588]

[0589] 3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethylacetate (10 mL) were combined and stirred for 10 min.(R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resultingsuspension was stirred at room temperature overnight. The solid wasfiltered and the filtrate washed with 1N NaOH. The aqueous phase wasacidified and extracted with EtOAc. The resulting organic phase wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the residue by preparative plate chromatography (silicagel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the product (338 mg, 46%,MH⁺=267).

Preparative Example 2

[0590]

[0591] Step A

[0592] 3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA,26 mL) in anhydrous CH₂Cl₂ (125 mL) were combined and stirred at 25° C.for 30 min. (R)-(+)-3-pyrrolidinol (8.7 g) in CH₂Cl₂ (25 mL) was addedover 25 min and the resulting suspension was stirred at room temperatureovernight. The mixture was extracted with 1M NaOH (aq) and the organicphase was discarded. The aqueous phase was acidified with 1M HCl (aq),extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the crude product (7 g) which was usedwithout further purification.

[0593] Step B

[0594] The crude product from Step A above was stirred with 10% Pd/C(0.7 g) in MeOH (100 mL) under a hydrogen gas atmosphere overnight. Thereaction mixture was filtered through celite, the filtrate concentratedin vacuo, and the resulting residue purified by column chromatography(silica gel, 10% MeOH/CH₂Cl₂ saturated with NH₄OH) to give the product(2.5 g, 41%, MH+=223).

Preparative Example 2.1

[0595]

[0596] To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH₂Cl₂ (10 mL)was added benzylisocyanate (3 mmol). After stirring for 2 hrs, aminescavenger resin (1.9 mmol) was added and the mixture was stirredovernight, filtered, the resin back-washed with CH₂Cl₂ and methanol, andthe organics concentrated in vacuo. Stirring of the crude material in 4NHCl/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave thetitle compound (41%, MH+=369).

Preparative Example 2.2-2.6

[0597] Following the procedures set forth in Preparative Example 2.1 butusing the isocyanate (or chloroformate) indicated in the Table below,the amines were obtained and used without further purification. Prep Ex.Amine Isocyanate Amine 2.2

2.3

2.4

2.5

2.6

Preparative Example 2.7

[0598]

[0599] To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH₂Cl₂ (30 mL)was added trifluoromethanesulfonic anhydride (5 mmol) and the mixturewas stirred overnight. The mixture was concentrated in vacuo, dilutedwith CH₂Cl₂ (10 mL) and treated with trifluoroacetic acid (10 mL). Afterstirring for 2 hr, the mixture was concentrated in vacuo to give thetitle compound (43%, MH+=233.1).

Preparative Example 2.8

[0600]

[0601] Step A

[0602] 3-Nitrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol)were added to a solution of 2% DMF/CH₂Cl₂, followed by DCC (5 mmol).After stirring for 2 hr, the mixture was filtered and concentrated invacuo and the residue used directly in Step B.

[0603] Step B

[0604] The product from Step A above was suspended in DMF and to thiswas added morpholino-2-carboxylic acid HCl (5 mmol) in CH₂Cl₂ (10mL)/DMF (5 mL) and diisopropylethylamine (10 mmol). The mixture wasstirred overnight, filtered, basified with 1N NaOH (50 mL), washed withCH₂Cl₂, acidified with 5N HCl and extracted with EtOAc. The organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo to givethe desired compound which was used directly in Step C (MH+=296).

[0605] Step C

[0606] Following a similar procedure as in Preparative Example 2 Step B,but using the product from Step B above, the title compound was obtained(23%, MH+=267).

Preparative Example 2.9

[0607]

[0608] Step A

[0609] 2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine werestirred with triethylamine and MeOH. After stirring overnight at reflux,the mixture was filtered and concentrated in vacuo to give the desiredcompound which was used directly in Step B (MH+=209).

[0610] Step B

[0611] Following a similar procedure as Preparative Example 2.8, Step Bexcept using the product from Preparative Example 2.9 Step A above, thedesired compound was obtained (41%, MH+=374).

[0612] Step C

[0613] Following a similar procedure as in Preparative Example 2, StepB, but using the product from Step B above, the desired compound wasobtained (99%, MH+=344).

Preparative Example 2.10

[0614]

[0615] Step A

[0616] Following a similar procedure as Preparative Example 2.8, Step Aexcept using 3-nitrobenzoic acid, the desired compound was obtained andused directly in Step B.

[0617] Step B

[0618] Following a similar procedure as Preparative Example 2.8, Step Bexcept using the products from Preparative Example 2.9, Step A andPreparative Example 2.10, Step A, the desired compound was obtained(86%).

[0619] Step C

[0620] Following a similar procedure as in Preparative Example 2, StepB, but using the product from Step B above, the desired compound wasobtained (67%, MH+=331).

Preparative Example 2.11

[0621]

[0622] Step A

[0623] N-Benzylpiperidone (2 g, HCl salt, hydrate) was stirred with THF(20 mL), concentrated to dryness, and placed under high vac. The residuewas diluted in THF (20 mL), and methyllithium was added (2.5 eq of 1.6Nin Et₂O) via syringe. After stirring for 3 hr, the mixture wasconcentrated in vacuo, diluted with water, extracted with CH₂Cl₂, anddried over Na₂SO₄. Filtration and concentrating in vacuo gave thedesired product (50%, MH+=205).

[0624] Step B

[0625] Following a similar procedure as in Preparative Example 2, StepB, but using the product from Step A above, the title compound wasobtained (95%, MH+=116).

Preparative Example 2.12

[0626]

[0627] Step A

[0628] To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL)was added concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and2-propanol (2 mL). After stirring at reflux overnight, the mixture wasconcentrated in vacuo, diluted with water, basified to pH 14 andextracted with ether. The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired product (98%) which wasused directly in Step B.

[0629] Step B

[0630] The product from Step A above (500 mg) was dissolved in MeOH (20mL) and to this was added NaBH₄ (50 mg). After stirring for 10 min, thesolution was concentrated in vacuo to give the desired compound whichwas used directly in Step C without purification.

[0631] Step C

[0632] The product from Step B above was diluted with MeOH (20 mL) andto this was added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) andthe mixture stirred under H₂ atmosphere (balloon) overnight. The mixturewas filtered, 4N HCl in dioxane (1 mL) was added, and the mixture wasconcentrated in vacuo to give the desired compound that was useddirectly without purification.

Preparative Example 2.13

[0633]

[0634] Step A

[0635] Following a similar procedure as Preparative Example 2, Step Aexcept using methyl glycinate, the desired ester was obtained. Themixture was poured into 200 mL of 1N NaOH, then extracted withdichloromethane. The pH was adjusted to 1 and NaCl was added untilsaturation. After several hours, the resulting precipitate was filteredand washed with cold water to give the desired product (42%).

[0636] Step B

[0637] Following a similar procedure as in Preparative Example 2 Step B,but using the product from Step A above, the title compound was obtained(95%).

Preparative Example 2.14

[0638]

[0639] Step A

[0640] Following a similar procedure as in Preparative Example 2.13,Step A except using methyl N-methylglycinate, the desired product wasobtained (18%).

[0641] Step B

[0642] Following a similar procedure as in Preparative Example 2, StepB, but using the product from Step A above, the title compound wasobtained (95%, MH+=225).

Preparative Example 2.15

[0643]

[0644] The cyclobutenedione intermediate from Preparative Example 87(200 mg), DIEA (100 ul), 3-aminosalicylic acid (120 mg) and EtOH (4 ml)were combined and heated to reflux overnight to give the title compound(90%, MH+=367).

Preparative Example 2.16

[0645]

[0646] The above n-oxide (2 g) was combined with H₂NMe/H₂O (15 cm³) andheated to 140° C. overnight. Potassium carbonate (1.3 g) added and themixture concentrated in vacuo. Extraction with EtOH and concentration ofthe filtrate in vacuo gave 1.56 g of crude amine (MH+=125).

Preparative Example 3-10.50

[0647] Following the procedures set forth in Preparative Examples 1-2but using the carboxylic acid, amine, and coupling agent [DCC (Prep.Ex. 1) or PyBrop (Prep. Ex. 2)] listed in the Table below, the indicatedamide products were obtained and used without further purification. 1.Coupling Agent Prep Carboxylic 2. % Yield Ex. acid Amine Product 3. MH⁺ 3

1. PyBrop 2. 87%, 86% 3. 181  4

1. PyBroP 2. 49% 3. 209  5

NH₃

1. PyBroP 2. 95% 3. 153  6

1. PyBroP 2. 83% 3. 167  7

1. PyBroP 2. 76% 3. 223  8

1. PyBroP 2. 65, 53 3. 209  9

1. PyBroP 2. 59, 69 3. 207 10

1. PyBroP 2. 49, 86 3. 237 10.1

1. PyBroP 2. 30, 88 3. 193 10.2

1. PyBroP 2. 26, 87 3. 195 10.3

1. PyBroP 2. 38 3. 209 10.4

1. PyBroP 2. 29 3. 209 10.5

1. PyBroP 2. 38 3. 223 10.6

1. PyBroP 2. 32, 99 3. 367.9 10.7

1. PyBroP 2. 35, 99 3. 237 10.8

1. DCC 2. 30, 99 3. 269 10.9

1. PyBroP 2. 58, 95 3. 233.1 10.10

1. PyBroP 2. 42, 95 3. 238.9 10.13

1. PyBroP 2. 51, 95 3. 307 10.14

1. PyBroP 2. 55 3. 347 10.15

1. PyBroP 2. 41 3. 369.1 10.16

1. PyBroP 2. 56 3. 354.9 10.17

1. PyBroP 2. 56 3. 308 10.18

1. PyBroP 2. 10, 95 3. 252.9 10.19

1. PyBroP 2. 42, 95 3. 249 10.20

1. PyBroP 2. 15, 95 3. 264.9 10.21

1. PyBroP 2. 64, 95 3. 273 10.22

1. PyBroP 2. 45, 95 3. 273 10.23

1. PyBroP 2. 44, 95 3. 281 10.24

1. PyBroP 2. 41, 95 3. 281.1 10.25

1. PyBroP 2. 48, 95 3. 257 10.26

1. DCC 2. 15, 99 3. 235 10.28

1. PyBroP 2. 52, 95 3. 237.1 10.29

1. PyBroP 2. 31, 95 3. 259.1 10.30

1. PyBroP 2. 54, 95 3. 250.9 10.31

1. PyBroP 2. 64, 95 3. 210.9 10.32

1. PyBroP 2. 47, 95 3. 197 10.33

1. PyBroP 2. 47, 95 3. 273 10.34

1. PyBroP 2. 51, 95 3. 237.1 10.35

1. PyBroP 2. 60, 90 3. 224 10.36

1. PyBroP 2. 65, 99 3. 252 10.37

1. PyBroP 2. 58, 99 3. 239 10.38

1. PyBroP 2. 35, 99 3. 221.1 10.39

1. PyBroP 2. 42, 99 3. 235.2 10.40

1. DCC 2. 32, 99 3. 293.1 10.41

1. PyBroP 2. 45, 99 3. 223.1 10.42

1. PyBroP 2. 55, 81 3. 251.1 10.43

1. PyBroP 2. 68, 66 3. 224.9 10.44

1. PyBroP 2. 68, 66 3. 241.1 10.45

1. PyBroP 2. 44, 40 3. 295 10.46

1. DCC 2. 37, 81 3. 265 10.47

1. PyBroP 2. 71, 95 3. 293.1 10.48

1. PyBroP 2. 35, 99 3. 220.9 10.49

1. DCC 2. 16, 99 3. 209.0 10.50

1. DCC 2. 18, 99 3. 264.0

Preparative Example 10.55 Alternative Procedure for Preparative Example3

[0648]

[0649] To the nitrosalicylic acid (3 g) dissolved dichloromethane (150mL) at room temperature was added oxalyl chloride (4.3 mL) and DMF (0.01eq.). After stirring for one day the mixture was concentrated in avacuum to give a semi solid which was used directly in step B.

[0650] To the material from step A diluted in dichloromethane (50 mL)and cooled to 0° C. was added dimethyl amine in THF (2N solution, 24.6mL) and triethylamine (4 eq.). After stirring for 24 hours at roomtemperature the mixture was concentrated in vacuo, diluted with 1Msodium hydroxide (30 mL) and after a half hour was washed withdichloromethane. The aqueous phase was acidified with 6M HCl (aq),extracted with dichloromethane and the organic phase was washed withwater, dried over Na₂SO₄ and concentrated to give the title compound(3.2 g, 93%).

[0651] A mixture of the product from step B above (6 g), 10% Pd/C (0.6g), and EtOH (80 mL) was stirred in a parr shaker under hydrogen (40psi) at room temperature for 2 days. Filtration through celite andconcentration in vacuo afforded the title product (5.1 g, 99%, MH⁺=181).

Preparative Example 11

[0652]

[0653] Step A

[0654] Following a similar procedure as in Preparative Example 1 exceptusing dimethylamine (2M in THF, 33 mL) and 5-methylsalicylic acid (5 g),the desired product was prepared (6.5 g).

[0655] Step B

[0656] Nitric acid (0.8 mL) in H₂SO₄ was added to a cooled (−20° C.)suspension of the product from Step A above (3 g) in H₂SO₄ (25 mL). Themixture was treated with 50% NaOH (aq) dropwise, extracted with CH₂Cl₂,dried over anhydrous MgSO₄, filtered and concentrated in vacuo to givethe product as a crude solid (2.1 g, 44%, MH⁺=225).

[0657] Step C

[0658] The product was prepared in the same manner as described in StepB of Preparative Example 2 (0.7 g, 99%, MH⁺=195).

Preparative Example 11.1

[0659]

[0660] Step A

[0661] The above amine was reacted with the acid using the procedure setforth in Preparative Example 2, Step A to yield the desired amide (54%).

[0662] Step B

[0663] Na₂S₂O₄ (1.22 g) was dissolved in water (4 ml) followed by theaddition of NH₃/H₂O (300 ul). The solution ws then added to the productfrom Step A (200 mg) in dioxane (4 ml) and stirred for 30 min. The crudematerial was purified via flash column chromatography (CH₂Cl₂/MeOH,20:1) to give 100mg of product (56%, MH+=251).

Preparative Example 11.2

[0664]

[0665] Following the procedures set forth in Preparative Example 11.1,Steps A and B, but using N-methylmethoxylamine, the title compound wasobtained (86%, MH+=181).

Preparative Example 11.10

[0666]

[0667] Step A

[0668] Following the procedure set forth in Preparative Example 1, butusing N-hydroxysuccinimide and 2% DMF in CH₂Cl₂, the desired amide wasobtained (33%, MH+=297).

[0669] Step B

[0670] Following the procedure set forth in Preparative Example 2, StepB, the amine was prepared (99%, MH+=267).

Preparative Example 11.11-11.18

[0671] Following the procedures set forth in Preparative Examples 11.11but using the carboxylic acid, amine, and coupling agent DCC indicated,the indicated amide products were obtained and used without furtherpurification. Prep Carboxylic 1. % Yield Ex. acid Amine Product 2. MH⁺11.11

1. 45, 92 2. 310.0 11.12

1. 45, 95 2. 247.2 11.13

1. 85, 85 2. 251.1 11.14

1. 99, 92 2. 211.1 11.15

1. 48, 84 2. 265 11.16

1. 78, 91 2. 238.1 11.17

1. 67, 90 2. 265.1 11.18

1. 28, 99 2. 2.267

Preparative Example 12

[0672]

[0673] Step A

[0674] Following a similar procedure as described in Preparative Example2 Step A except using dimethylamine in place of R-(+)-3-pyrrolidinol,the desired product was prepared.

[0675] Step B

[0676] The product from step A above (8 g) was combined with iodine (9.7g), silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirredovernight. Filtration, concentration of the filtrate, re-dissolution inCH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo to affordthe product (7.3 g, 57%, MH⁺=337).

[0677] Step C

[0678] The product from Step B above (3.1 g) was combined with DMF(50mL) and MeI (0.6 mL). NaH (60% in mineral oil, 0.4 g) was addedportionwise and the mixture was stirred overnight. Concentration invacuo afforded a residue which was diluted with CH₂Cl₂, washed with 1MNaOH (aq), dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification through a silica gel column (EtOAc/Hex, 1:1) gavethe desired compound (1.3 g, 41%, MH⁺=351).

[0679] Step D

[0680] The product from Step D above (200 mg), Zn(CN)₂ (132 mg),Pd(PPh₃)₄ (130 mg) and DMF (5 mL) were heated at 80° C. for 48 hrs, thencooled to room temperature and diluted with EtOAc and 2M NH₄OH. Aftershaking well, the organic extract was dried over anhydrous MgSO₄,filtered, concentrated in vacuo and purified by preparative platechromatography (Silica, EtOAc/Hex, 1:1) to give the desired compound (62mg, 44%, MH⁺=250).

[0681] Step E

[0682] BBr₃ (1.3 mL, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (5 mL)of the product from step D above (160 mg) and stirred for 30 min. Themixture was diluted with water, extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to give the desiredcompound (158 mg, MH⁺=236).

[0683] Step F

[0684] A mixture of the product from step E above (160 mg), platinumoxide (83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40psi) for 1.5 hr. Filtration through celite and concentration in vacuoafforded the product (165 mg, MH⁺=206).

Preparative Example 12.1

[0685]

[0686] Step A

[0687] Following a similar procedure as in Preparative Example 2, Step Aexcept using 3-(methylaminomethyl)pyridine and 3-nitrosalicylic acid,the desired compound was prepared (41%).

[0688] Step B

[0689] The compound from Step A above ( 0.3 g) was diluted withchloroform (15 mL) and stirred with mCPBA (0.4 g) for 2 hr. Purificationby column chromatography (silica, 10% MeOH/CH₂Cl₂) gave the pyridylN-oxide (0.32 g, 100%, MH⁺=303.9).

[0690] Step C

[0691] Following a similar procedure as in Preparative Example 11.1,Step B, but using the product from Step B above, the desired compoundwas obtained (15%, MH+=274).

Preparative Example 12.2

[0692]

[0693] Step A

[0694] 3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentratedH₂SO₄ (1 mL) were stirred at reflux overnight, concentrated in vacuo,diluted with CH₂Cl₂, and dried over Na₂SO₄. Purification by columnchromatography (silica, 5% MeOH/CH₂Cl₂) gave the methyl ester (2.8 g,65%).

[0695] Step B

[0696] Following a similar procedure as in Preparative Example 2, StepB, but using the product from Step A above, the desired compound wasobtained (95%, MH+=1 67.9).

Preparative Example 12.3

[0697]

[0698] To morpholine-2-carboxilic acid (200 mg) in EtOH (40 mL) at 0° C.was added acetyl chloride (3 mL) and the mixture was stirred at refluxovernight. Concentration in vacuo, dilution with CH₂Cl₂ and washing withNaHCO₃ (aq) gave the title compound (99%, MH⁺=160.1).

Preparative Example 12.4

[0699]

[0700] To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0°C. was added a solution of borane. THF complex (1N, 10.38 ml) and themixture was stirred for 30 min at 0° C., and for 2 hr at roomtemperature. Water (200 ml) was added to the reaction and the mixtureextracted with CH₂Cl₂, dried with Na₂SO₄, and concentrated in vacuo togive 490 mg of product (26%). The product was then stirred in 4NHCl/dioxane to give the amine salt.

Preparative Example 13

[0701]

[0702] Step A

[0703] Following a similar procedure as in Preparative Example 1 exceptusing dimethylamine (2M in THF, 50 mL) and 4-methylsalicylic acid (15g), the desired compound was prepared (6.3 g, 35%).

[0704] Step B

[0705] The product from step A above (1.5 g) was combined with iodine(2.1 g), NaHCO₃ (1.1 g), EtOH (40 mL) and water (10 mL) and stirredovernight. Filtration, concentration of the filtrate, re-dissolution inCH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification by flash column chromatography (silica gel, 0.5-0.7%MeOH/CH₂Cl₂) gave the product (0.5 g, 20%, MH⁺=306).

[0706] Step C

[0707] Nitric acid (3.8 mL) in AcOH (10 mL) was added to the productfrom Step B above (0.8 g) and the mixture was stirred for 40 min. Themixture was diluted with water and extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give the productas an orange solid (0.8 g, 92%, MH⁺=351).

[0708] Step D

[0709] A mixture of the product from step C above (800 mg), 10% Pd/C(100 mg), and EtOH/MeOH (40 mL) was stirred in a parr shaker underhydrogen (45 psi) for 1.5 hr. Filtration through celite andconcentration in vacuo afforded the title product after purification bypreparative plate chromatography (Silica, 10% MeOH/CH₂Cl₂, saturatedwith NH₄OH) to give the product (92 mg, 22%, MH⁺=195).

Preparative Example 13.1

[0710]

[0711] Step A

[0712] Following a similar procedure as in Preparative Example 2, Step Aexcept using dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid(5 g), the desired compound was prepared (4.2 g, 75%, MH+=244).

[0713] Step B

[0714] Nitric acid (10 ml) in AcOH (100 ml) was added to the productfrom Step A above (2 g) and the mixture was stirred for 20 min. Themixture was diluted with water and extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give the productas a yellow solid (1.9 g, 80%, MH+=289).

[0715] Step C

[0716] The product from Step B above (1.9 g) was partially dissolved inEtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O(5.74 g) was added and stirred at room temperature overnight. The crudereaction was concentrated in vacuo, diluted with CH₂Cl₂ and washed withNaHCO₃, dried over anhydrous MgSO₄, filtered and concentrated in vacuoto give the product as a solid (185 mg, 9%, MH+=259).

Preparative Example 13.2

[0717]

[0718] Step A

[0719] Following a similar procedure as in Preparative Example 2, StepA, except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylicacid (5 g), the desired compound was prepared (4.5 g, 78%, MH+=200).

[0720] Step B

[0721] Nitric acid (10 ml) in AcOH (100 ml) was added to the productfrom Step A above (2 g) and the mixture was stirred for 20 min. Themixture was diluted with water and extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give the productas a solid (2.2 g, 88%, MH+=245).

[0722] Step C

[0723] The product from Step B above (2.2 g) was partially dissolved inEtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O(7.01 g) was added and stirred at room temperature overnight. The crudereaction was concentrated in vacuo, diluted with CH₂Cl₂ and neutralizedwith NaOH. The entire emulsion was filtered though celite, the layerswere separated and the organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo to give a solid (540 mg, 22%,MH+=215).

Preparative Example 13.3

[0724]

[0725] Step A

[0726] 3-Nitrosalicylic acid (10 g), PyBroP (20.52 g), and DIEA (28 ml)in anhydrous CH₂Cl₂ (200 ml) were combined and stirred at roomtemperature for 10 min. Dimethylamine (2M in THF, 55 ml) was added andlet the reaction stir over the weekend. The mixture was extracted with1N NaOH (aq) and the organic phase was discarded. The aqueous phase wasacidified with 1N HCl (aq), extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The oil was taken up in etherand a solid crashed out, triterated in ether to give 4.45 g of a solid(39%, MH+=211).

[0727] Step B

[0728] The product from Step A (2.99 g), K₂CO₃ (9.82 g), and iodomethane(8.84 ml) were combined in acetone and heated to reflux overnight. Thereaction was filtered and concentrated in vacuo. The oil was taken up inCH₂Cl₂ and washed with 1N NaOH, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

[0729] Step C

[0730] The crude product from Step B (3.3 g) was stirred with 10% Pd/C(350 mg) in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psiovernight. The reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to give 2.34 g of a solid (85%,MH+=195).

[0731] Step D

[0732] The product from Step C (469 mg) was dissolved in AcOH (6 ml).1.95M Br₂ in AcOH (1.23 ml) was added dropwise to the reaction and themixture was stirred at room temperature for 1 hour. 50% NaOH was addedto the reaction at 0° C. and the mixture was extracted with CH₂Cl₂,dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude mixture was purified by preparative plate chromatography (Silica,5% MeOH/CH₂Cl₂) to give the desired product (298 mg, 23%, MH+=273).

[0733] Step E

[0734] BBr₃ (2.14 ml, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (8ml) of the product from Step D above (290 mg) and stirred overnight. Asolid formed and was filtered, taken up in MeOH/CH₂Cl₂ and purified bypreparative plate chromatography (Silica, 5% MeOH/CH₂Cl₂) to give thedesired product (137 mg, 49%, MH+=259).

Preparative Example 13.4

[0735]

[0736] Step A

[0737] To the product from Preparative Example 13.3 Step D (200 mg) wasadded phenylboronic acid (98 mg), PdCl₂(PPh₃)₂ (51 mg), and Na₂CO₃ (155mg) in THF/H₂O (4 ml/1 ml). The solution was heated at 80° C. overnight.EtOAc was added to reaction and washed with 1N NaOH. The organic layerwas dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude mixture was purified by preparative plate chromatography (5%MeOH/CH₂Cl₂) to give 128 mg of an oil (65%, MH+=271).

[0738] Step B

[0739] Following a similar procedure as in Preparative Example 13.3 StepE and using the product from Step A above, the desired compound wasprepared (0.1 g, 69%, MH+=257.1).

Preparative Example 13.5-13.7

[0740] Following the procedures set forth in Preparative Example 13.4but using the boronic acid from the Preparative Example indicated in theTable below, the amine products were obtained. 1. Yield (%) Prep Ex.Boronic Acid Product 2. MH⁺ 13.5

1. 15% 2. 258 13.6

1. 32% 2. 325 13.7

1. 18% 2. 325

Preparative Example 13.8

[0741]

[0742] Step A

[0743] 2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylaminehydrochloride (1.73 g) were combined in anhydrous toluene and heated to99° C. overnight. After the reaction cooled down, product was extractedwith H₂O. Aqueous layer was acidified with conc. HCl dropwise giving aprecipitate, which was filtered to give the product (597 mg, 87%,MH+=163).

[0744] Step B

[0745] Nitric acid (0.034 ml) in AcOH (5 ml) was added to the productfrom Step A above (100 mg) in AcOH and the mixture was allowed to stirfor 1 hr. CH₂Cl₂ and H₂O were added to reaction. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo to givean oil. Trituration in ether gave the product as a solid (12 mg, 9%,MH+=208).

[0746] Step C

[0747] The product from step C (56 mg) was stirred with 10% Pd/C (20 mg)in EtOH/MeOH (15 ml) under a hydrogen gas atmosphere overnight. Thereaction mixture was filtered through celite, the filtrate wasconcentrated in vacuo to give 29 mg is of a solid (62%, MH+=178).

Preparative Example 13.9

[0748]

[0749] The amine was prepared following the procedure disclosed in WOPatent Application 01/68570.

Preparative Example 13.10

[0750]

[0751] The amine was prepared following the procedure disclosed in WOPatent Application 01/68570.

Preparative Example 13.11

[0752]

[0753] Step A

[0754] Following the procedure described in Preparative Example 88.2,Step A, the ketone was prepared (6.4 g, 36%).

[0755] Step B

[0756] To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml)in anhydrous toluene (20 ml) was added 1N TiCl₄ in toluene (3 ml) atroom temperature for 1.5 hrs. The precipitate was filtered and thefiltrate was concentrated in vacuo and purified via flash columnchromatography (Hex/EtOAc, 18/1) to give 800 mg of product (71%).

[0757] Step C

[0758] The imine from above (760 mg) and DBU (800 ul) were stirredwithout solvent for 4 hr. The crude reaction was concentrated in vacuoand purified via flash column chromatography (Hex/EtOAc, 8/1) to give600 mg of product (79%).

[0759] Step D

[0760] The imine from Step C (560 mg) was dissolved in ether (8 ml). 3NHCl (5 ml) added and let stir at room temperature overnight. The etherlayer was separated and concentrated in vacuo to give 400 mg of theamine hydrochloride product (93%).

Preparative Example 13.12

[0761]

[0762] The title compound was prepared similarly as in PreparativeExample 13.11, but using the 2-S-methylbenzylamine instead of2-R-methylbenzylamine (69%).

Preparative Example 13.13

[0763]

[0764] Step A

[0765] At room temperature, CsF (60 mg) was added to a mixture offurfuraldehyde (1.3 ml) and TMS-CF₃ (2.5 g) and stirred at roomtemperature (24 h) and refluxed for another 12h. 3N HCl (40 ml) wasadded and after 4 hr, the mixture was extracted with ether, washed withbrine, dried over MgSO₄, and concentrated in vacuo to give the product(2.6 g, 100%).

[0766] Step B

[0767] To a solution of alcohol from above (2.6 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (10 g) portionwise and 1 dropof water. After stirring for 3 hr at room temperature, 10% Na₂S₂O₃ (60ml) was added and after stirring overnight, the solid was filtered offand the filtrate was extracted with CH₂Cl₂. The organic layer was washedwith saturated sodium bicarbonate, dried with MgSO₄, filtered andconcentrated in vacuo. Ether/hexane (1:2; 30 ml) was added to theresidue, filtered, and filtrate concentrated in vacuo to give theproduct (2 g, 78%).

[0768] Step C

[0769] Following the procedures described in Preparative Example 13.11,Steps B, C and D, the amine salt was prepared.

Preparative Examples 13.15-13.17B

[0770] Following the procedure set forth in Preparative Example 13.13,but using the prepared or commercially available aldehydes, theoptically pure amine products in the Table below were obtained. Prep Ex.Aldehyde Amine Product Yield (%) 13.15

20% 13.16

31% 13.17

66% 13.17A

38% 13.17B

31%

Preparative Example 13.18

[0771]

[0772] The title compound was prepared from trifluorophenylketoneaccording to the procedures described in Preparative Example 13.11,Steps B, C, and D (68%).

Preparative Example 13.19

[0773]

[0774] Step A

[0775] Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g,217.4 mmol) was added followed by a solution of iodomethane (14.5 mL,233.0 mmol). The mixture was heated to reflux and continued for 6 h.After cooled to room temperature, the mixture was filtered, the solidmaterial was rinsed with acetone (˜200 mL). The filtrate and rinsingwere concentrated under reduced pressure to a solid, further dried onhigh vacuum, yielding 13.7 g (100%) ofmethyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH⁺=251.0).

[0776] Step B

[0777] Methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (13.7 g),available from step A, was dissolved in 75 mL of THF, and added with a1.0 M sodium hydroxide aqueous solution (65 mL, 65.0 mmol). The mixturewas stirred at room temperature for 24 h. A 1.0 M hydrogen chlorideaqueous solution was added dropwise to the mixture until pH wasapproximately 2. The acidic mixture was extracted with CH₂Cl₂ (100 mL×2,50 mL). The combined organic extracts were washed with brine (40 mL),dried with Na₂SO₄, and concentrated under reduced pressure to a solid,10.0 g (100%, over two steps) of 3-methoxy-4-bromo-2-thiophenecarboxylicacid (MH⁺=237.0).

[0778] Step C

[0779] To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylicacid (6.5 g, 27.4 mmol) in 140 mL of CH₂Cl₂, obtained from step B, wasadded bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, themixture was diluted with 100 mL of CH₂Cl₂, and washed with a 1.0 Msodium hydroxide aqueous solution (30 mL×3) and brine (30 mL). Theorganic solution was dried with Na₂SO₄, filtered, and concentrated to anoil. This crude oil product was purified by flash column chromatography,eluting with CH₂Cl₂-hexanes (1:1, v/v). Removal of solvents afforded asolid, further dried on high vacuum, yielding 6.76 g (93%) ofN,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH⁺=265.0,M+2=266.1).

[0780] Step D

[0781] An oven dried three-neck round bottom flask was equipped with arefluxing condenser, charged sequentially with palladium acetate (95 mg,0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol), cesium carbonate (9.2 g,28.33 mmol), and N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide(3.74 g, 14.2 mmol, from step C). The solid mixture was flushed withnitrogen. Toluene (95 mL) was added to the solid mixture followed bybenzophenone imine (3.6 mL, 21.5 mmol). The mixture was heated to refluxand continued for 10 h. A second batch of palladium acetate (95 mg, 0.42mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 mL of toluene was added.Refluxing was continued for 14 h. The third batch of palladium acetate(30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, andreaction continued at 110° C. for 24 h. The mixture was cooled to roomtemperature, diluted with ether (50 mL), filtered through a layer ofCelite, rinsing with ether. The filtrate and rinsing were concentratedunder reduced pressure to an oil, which was purified twice by flashcolumn chromatography using CH₂Cl₂ and CH₂Cl₂-MeOH (200:1) as eluents.Removal of solvents afforded 4.1 g (79%) of the amido-thiophenediphenylimine product as a solid (MH⁺=365.1).

[0782] Step E

[0783] To a stirred solution of thiophene imine (5.09 g, 13.97 mmol),obtained from step D, in 140 mL of CH₂Cl₂ at −78° C. was added dropwisea 1.0 M solution of boron tribromide in CH₂Cl₂. The mixture was stirredfor 3 h while the temperature of the cooling bath was increased slowlyfrom −78° C. to −15° C. 100 mL of H₂O was added, the mixture was stirredat room temperature for 30 min, then the two layers were separated. Theorganic layer ( as A) was extracted with H₂O (30 mL×2). The aqueouslayer and aqueous extracts were combined, washed with CH₂Cl₂ (30 mL),and adjusted to pH ˜8 using a saturated NaHCO₃ aqueous solution. Theneutralized aqueous solution was extracted with CH₂Cl₂ (100 mL×3), theextracts were washed with brine, dried with Na₂SO₄, and concentratedunder reduced pressure to a light yellow solid, 1.49 g ofN,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). Theprevious separated organic layer A and organic washing were combined,stirred with 30 mL of a 1.0 M HCl aqueous solution for 1 h. The twolayers were separated, the aqueous layer was washed with CH₂Cl₂ (30 mL)and adjusted to pH ˜8 using a saturated NaHCO₃ aqueous solution, and theseparated organic layer and organic washing were combined as organiclayer B. The neutralized aqueous solution was extracted with CH₂Cl₂ (30mL×4), the extracts were washed with brine, dried by Na₂SO₄, andconcentrated under reduced pressure to give 0.48g of a solid as thesecond crop of the titled product. Organic layer B from above was washedwith brine, and concentrated to an oil, which was separated bypreparative TLC (CH₂Cl₂-MeOH=50:1) to afford 0.45 g of a solid as thethird crop of the titled product. The overall yield of the product,N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide, is 2.32 g (89%)(MH⁺=187.0).

Preparative Example 13.20

[0784]

[0785] Step A

[0786] To the product from Preparative Example 13.19 Step D (1.56 g) inCH₂Cl₂ (55 ml) was added potassium carbonate (1.8 g) followed bydropwise addition of bromine (0.45 ml). After 5 hr of mixing, water (100ml) was added to the reaction and the layers were separated. The aqueouslayer was extracted with CH₂Cl₂, which was then washed with brine,saturated sodium bicarbonate, and brine again. The organic layer wasdried with Na₂SO₄, and concentrated in vacuo. The residue was purifiedvia flash column chromatography (CH₂Cl₂) to yield 1.6 g of product(83%).

[0787] Step B

[0788] The product from above was reacted in the procedure set forth inPreparative Example 13.19 Step C to give the amine.

Preparative Example 13.21

[0789]

[0790] Step A

[0791] To the product from Preparative Example 13.20, Step A (300 mg) inTHF (7 ml) at −78° C. was added a solution of n-BuLi (1.6M in hexanes,0.54 ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3hrs of stirring at −78° C., the reaction was warmed to room temperatureovernight. Saturated ammonium chloride and water were added to thereaction and extracted with CH₂Cl₂. The organic layer was washed withsaturated sodium bicarbonate and brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by preparativeplate chromatography (CH₂Cl₂-MeOH=70:1 to 50:1) to afford the product(111 mg, 43%).

[0792] Step B

[0793] The product from above was reacted in the procedure set forth inPreparative Example 13.19, Step E to give the amine.

Preparative Example 13.22

[0794]

[0795] Step A

[0796] To the product from Preparative Example 13.19 (400 mg), Step D inCH₂Cl₂-pyridine (14 ml) was added N-chlorosuccinimide (220 mg). Themixture was stirred for 5 hr and then diluted with CH₂Cl₂ and washedwith water, saturated sodium bicarbonate and brine, and concentrated invacuo. The crude product was purified via preparative platechromatography (CH₂Cl₂-MeOH=50:1) to give 180 mg of product (64%).

[0797] Step B

[0798] The product from above (274 mg) was reacted in the procedure setforth in Preparative Example 13.19, Step E to give the amine (89 mg,58%).

Preparative Example 13.23

[0799]

[0800] Step A

[0801] To a stirred solution of acid (630 mg) from Preparative Example13.19, Step B in CH₂Cl₂ (25 ml) was added oxalyl chloride (235 ul)followed by a catalytic amount of DMF (10 ul). The mixture was stirredfor 1 hr, then potassium carbonate (1.8 g) was added followed by3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight andwas quenched with water (25 ml). Layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by preparative platechromatography (CH₂Cl₂) to afford the product (580 mg, 78%,MH+=317,319).

[0802] Step B

[0803] The acid from the above (750 mg) step was reacted following theprocedure set forth in Preparative Example 13.3, Step B to yield 625 mgof product (80%, MH+=331).

[0804] Step C

[0805] The product from above was reacted following the procedure setforth in Preparative Example 13.19, Step D to yield 365 mg of product(53%)

[0806] Step D

[0807] The product from above was reacted following the procedure setforth in Preparative Example 13.19, Step E to give the amine product(MH+=254).

Preparative Example 13.25

[0808]

[0809] Step A

[0810] To a solution of 2-methylfuran (1 g) in ether (30 ml) was addedn-BuLi (5.32 ml) at −78° C. The reaction was warmed to room temperatureand then refluxed at 38° C. for 1 hr. The reaction was cooled back downto −78° C. where the furyl lithium was quenched withtrifluorobutyraldehyde and let stir at room temperature overnight.Saturated ammonium chloride added and extracted with ether. Purified viaflash column chromatography to yield pure product (2 g, 80%)

[0811] Step B

[0812] The azide was prepared using the procedure from PreparativeExample 75.75, Step B and the alcohol (1 g) from above and carried oncrude to Step C below.

[0813] Step C

[0814] The amine was prepared using the procedure from PreparativeExample 75.75, Step C to yield 400 mg of an oil (53%).

Preparative Example 13.26

[0815]

[0816] Step A

[0817] Perfluoroiodide (3.6 ml) was condensed at −78° C. Ether (125 ml)was added followed by the methyllithium.lithiumbromide complex (1.5M inether, 18.4 ml). After 15 min, a solution of 5-methylfuraldehyde (2.5ml) in ether was added dropwise. The reaction was warmed to 45° C. andlet stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml)were added and let stir at room temperature for 1 hr. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried with Na₂SO₄, filtered andconcentrated in vacuo to give 5.86 g of product (100%).

[0818] Step B

[0819] The alcohol from above was reacted to form the azide using theprocedure set forth in Preparative Example 75.75 Step B.

[0820] Step C

[0821] The azide from above was reacted to form the racemic amine usingthe procedure set forth in Preparative Example 75.75 Step C.

Preparative Example 13.27

[0822]

[0823] Step A

[0824] Following the procedure set forth in Preparative Example 13.26,Step A, the alcohol was prepared (100%).

[0825] Step B

[0826] To a solution of the alcohol (500 mg) from step A above in CH₂Cl₂(20 ml) was added N-methyl-morpholine monohydrate (575 mg) and acatalytic amount of tetrapropyl ammonium perruthenate (76 mg). After 3hr, the mixture was diluted with hexane (10 ml) and filtered through asilica pad, rinsing with hexane: CH₂Cl₂ (200 ml). The filtrate wasconcentrated in vacuo to give 350 mg of product (70.7%)

[0827] Step C

[0828] The ketone (1.19 g) from Step B was dissolved in THF (9.5 ml) andcooled to 0° C. A solution of S-methyl oxazoborolidine (1M in toluene, 1ml) followed by a solution of borane complexed with dimethylsulfide (9.5ml, 2M in THF) was added to the solution. The mixture was stirred at 0°C. for 30 min and continued at room temperature for 5 hr. The mixturewas cooled back down to 0° C. and methanol (15 ml) was added dropwise tothe mixture. After 30 min, the mixture was concentrated in vacuo to givean oily residue.

[0829] The residue was dissolved in CH₂Cl₂ and washed with 1N HCl,water, and brine. Dried with Na₂SO₄, filtered and concentrated in vacuo.The crude material was purified via flash column chromatography(Hex/CH₂Cl₂, 1:1) to afford 1.14 g of an oil (67%).

[0830] Step D

[0831] The alcohol (1.14 g) from above was reacted to form the azideusing the procedure set forth in Preparative Example 75.75 Step B.

[0832] Step E

[0833] The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg)in EtOH (40 ml) under a hydrogen gas atmosphere overnight. The reactionwas filtered through celite, the filtrate was concentrated in vacuo togive 700 mg of product (70%).

Preparative Example 13.28

[0834]

[0835] Step A

[0836] To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) inacetic anhydride (6 ml) at 0° C. was added dropwise a solution of fumingnitric acid in acetic acid (2 ml in 10 ml). After 30 min, the reactionwas warmed to room temperature and let stir for 5 hrs where a solidprecipitated out. Ice was added to the reaction and the solid wasfiltered. The solid was purified by flash column chromatography(Hex/CH₂Cl₂, 3:1 and 2:1) to yield 800 mg of desired product (20%).

[0837] Step B

[0838] The above nitro-thiophene compound (278 mg) was reduced using theprocedure set forth in Preparative Example 2, Step B to give 54 mg ofproduct (23%).

[0839] Step C

[0840] The above amine (395 mg), TEA (1 ml) and methanesulfonylchloride(0.5 ml) were combined in CH₂Cl₂ (35 ml) and stirred at room temperaturefor 1 hr. The reaction was quenched with saturated sodium bicarbonate(15 ml). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to afford product (854 mg, 100%).

[0841] Step D

[0842] To the above product (854 mg) in THF (25 ml) was added dropwise asolution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixturewas stirred overnight, then diluted with CH₂Cl₂ (30 ml), washed withammonium chloride and brine, dried over over Na₂SO₄, filtered andconcentrated in vacuo to afford product (2.36 g, >100%).

[0843] Step E

[0844] The ketone (2.36 g) above was reacted via the procedure set forthin Preparative Example 88.2, Step B to yield 547 mg of product (86.6%).

[0845] Step F

[0846] To the product from step E (310 mg) in dimethoxyethane (12 ml)was added dropwise a solution of LAH (1M in ether, 3.8 ml). The mixturewas heated to reflux overnight. The reaction was cooled to roomtemperature, SiO₂ was added as well as water (1 ml) dropwise and letstir for 15 min. The mixture was filtered and the filtrate wasconcentratred in vacuo. The crude product was purified by preparativeplate chromatography (MeOH/CH₂Cl₂, 15:1) to give the amine product (40mg, 14%).

Preparative Example 13.29

[0847]

[0848] Step A

[0849] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. Themixture was stirred for 15 min at −78° C. and 1.5 h at room temp.Afterwards, the mixture was poured carefully into crushed ice, andextracted with dichloromethane. The extracts were washed with brine,dried over magnesium sulfate, filtered through a 1-in silica gel pad.The filtrate was concentrated in vacuo to give the desired compound (4.2g).

[0850] Step B

[0851] The product from Step A above (4.5 g) was dissolved indichloromethane (140 mL) and added with triethylamine (8.8 mL) followedby diethyl amine in THF (2M, 21 mL). The resulting mixture was stirredat room temperature overnight. The mixture was washed with brine andsaturated bicarbonate (aq) and brine again, dried over sodium sulfate,filtered through a 1-in silica gel pad. The filtrate was concentrated invacuo to give the desired compound (4.4 g).

[0852] Step C

[0853] The product from Step B above (4.3 g) was dissolved indichloromethane (125 mL) and cooled in a −78° C. bath. A solution ofboron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. Themixture was stirred for 4 h while the temperature was increased slowlyfrom −78° C. to 10° C. H₂O was added, the two layers were separated, andthe aqueous layer was extracted with dichloro-methane. The combinedorganic layer and extracts were washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 3.96 g of thedesired hydroxy-compound.

[0854] Step D

[0855] The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with a 10% Na₂S₂O₃ aqueoussolution and brine, dried over sodium sulfate, and filtered through acelite pad. The filtrate was concentrated in vacuo to afford 4.2 g ofthe desired bromo-compound.

[0856] Step E

[0857] The product from Step D (4.2 g) was dissolved in 100 mL ofacetone and added with potassium carbonate (10 g) followed byiodomethane (9 mL). The mixture was heated to reflux and continued for3.5 h. After cooled to room temperature, the mixture was filteredthrough a Celite pad. The filtrate was concentrated in vacuo to a darkbrown residue, which was purified by flash column chromatography elutingwith dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desiredproduct.

[0858] Step F

[0859] The product from step E (2.7 g) was converted to the desiredimine compound (3 g), following the similar procedure to that ofPreparative Example 13.19 step D.

[0860] Step G

[0861] The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH˜6 using 3.0 Mand 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

Preparative Examples 13.30-13.32

[0862] Following the procedures set forth in Preparative Example 13.29,but using commercially available amines, hydroxy-amino-thiopheneproducts in the Table below were obtained. Yield (%) Prep Ex. AmineProduct MH⁺ 13.30 Bn₂NH

10% 375.1 13.31 MeBnNH

14% 299.0 13.32 EtBnNH

22% 13.32A (Et)₂NH

25%

Preparative Example 13.33

[0863]

[0864] Step A

[0865] 2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), theproduct from step A of Preparative Example 13.29, was converted to3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH⁺=312.1) byusing ethylbenzyl-amine, following the procedure set forth inPreparative Example 13.29, Step B.

[0866] Step B

[0867] The product from step A above (5.5 g, 17.70 mmol) wasdemethylated following the procedure set forth in Preparative Example13.29, Step C. The alcohol product was obtained in 4.55 g (87%,MH⁺=298.0).

[0868] Step C

[0869] The product from Step B above (4.55 g, 15.30 mmol) was brominatedusing the procedure set forth in Preparative Example 13.29, Step D. Thecorresponding bromide was obtained in 4.85 g (84%).

[0870] Step D

[0871] The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E. The product was obtained in 4.82 g (96%).

[0872] Step E

[0873] The product from Step D above (4.82 g, 12.36 mmol) was stirredwith concentrated sulfuric acid (5 mL) at room temperature for 3 h. Icewater (30 mL) was added to the mixture followed by CH₂Cl₂ (50 mL). Theaqueous mixture was adjusted to pH˜6 using a 1.0 M NaOH aqueoussolution. The layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to a dark brown oil, whichwas purified by flash column chromatography, eluting with CH₂Cl₂-hexanes(1:1, v/v). Removal of solvents afforded 3.03 g (82%) of thedebenzylated product (M⁺=300.0, M+2=302.0).

[0874] Step F

[0875] The product from Step E (1.34 g, 4.45 mmol) was methylated usingthe procedure set forth in Preparative Example 13.29, Step E. Thedesired product was obtained in 1.36 g (97%, M⁺=314.1, M+2 =316.0).

[0876] Step G

[0877] The product from Step F (1.36 g, 4.33 mmol) was converted toimine product (1.06 g, 55%, MH⁺=415.1) using the procedure set forth inPreparative Example 13.29, Step F.

[0878] Step H

[0879] The imine product from Step G (1.06 g, 2.56 mmol) was convertedto the desired hydroxy-amino thiophene compound (0.26 g, 43%) using theprocedure set forth in Preparative Example 13.29, Step G.

Preparative Example 13.34

[0880]

[0881] Step A

[0882] 2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), theproduct from step A of Preparative Example 13.29, was dissolved in 100mL of CH₂Cl₂ and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g,35.68 mmol) was added. The mixture was stirred for 20 h at roomtemperature, diluted with 100 mL of CH₂Cl₂, and washed with a 0.5 N HClaqueous solution (50 mL×2), H₂O (50 mL), and brine (50 mL). The organicsolution was dried with Na₂SO₄, and concentrated in vacuo to a brownoil. This oil was dissolved in 100 mL of CH₂Cl₂, washed again with a 0.5M HCl aqueous solution (30 mL×3) and brine. After dried over Na₂SO₄, theorganic solution was concentrated in vacuo to a yellow solid, 4.48 g(91%, MH⁺=275.0) of the desired product.

[0883] Step B

[0884] The product from Step A above (4.48 g, 16.33 mmol) was dissolvedin acetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol)and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at roomtemperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL ofCH2Cl2, and filtered through a 1-in silica gel pad, rinsing with CH₂Cl₂.The filtrate was concentrated under reduced pressure to give 4.23 g(90%, MH⁺=289.0) of the desired product as a light yellow solid.

[0885] Step C

[0886] To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol)in 8 mL of N,N′-dimethylforamide at room temperature was addedethanethiol (0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixturebecame a clear solution, and was added to a stirred solution of theproduct obtained from Step B above (0.45 g, 1.56 mmol) in 2 mL ofN,N′-dimethylforamide in a round bottom flask. The flask was sealed witha ground glass stopper, and the mixture was heated at 90-95° C. for 4 h.After cooled to room temperature, the mixture was poured into 20 mL of a1.0 M NaOH aqueous solution, further rinsed with 20 mL of H₂O. Theaqueous mixture was washed with diethyl ether (30 mL×2), adjusted toPH˜5 using a 0.5 M HCl aqueous solution, and extracted with CH₂Cl₂ (50mL×4). The combined extracts were washed with brine, dried (Na₂SO₄), andconcentrated to a dark yellow solution. This was dissolved in 50 mL ofethyl acetate, washed with H₂O (30 mL×2) and brine (30 mL), dried overNa₂SO₄. Evaporation of solvent gave 0.422 g of the alcohol product (99%,MH⁺=275.0).

[0887] Step D

[0888] The alcohol obtained from Step C above (0.467 g, 1.70 mmol) wasbrominated using the procedure set forth in Preparative Example 13.29,Step D, to afford the corresponding bromide in 0.607 g (100%).

[0889] Step E

[0890] The bromide obtained from Step D above (0.607 g, 1.72 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E, to give the desired product in 0.408 g (65%, M⁺=367, M+2=369.1).

[0891] Step F

[0892] The product (0.405 g, 1.103 mmol) from Step E above was convertedto the imine compound (0.29 g, 56%) using the procedure set forth inPreparative Example 13.29,Step F.

[0893] Step G

[0894] The imine product obtained from Step F above (0.29 g, 0.61 mmol)was demethylated using the procedure set forth in Step C above to givethe corresponding alcohol as a dark yellow oil, which was dissolved in 5mL methanol and added with sodium acetate (0.12 g, 1.46 mmol) andhydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixturewas stirred at room temperature for 3 h, and poured into 10 mL of 1.0 MNaOH aqueous solution. 30 mL of H₂O was used as rinsing and combined tothe aqueous layer. The aqueous mixture was washed with diethyl ether (40mL×3), adjusted to pH˜6 using a 1.0 M HCl aqueous solution, andextracted with ethyl acetate (40 mL×3). The organic extracts were washedwith H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, and concentratedin vacuo to give 0.112 g of the desired hydroxy-amino thiophenesulfonamide (64%, MH⁺=290).

Preparative Example 13.35

[0895]

[0896] Step A

[0897] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi(8.38 mL) at −78° C. and stirred at room temperature for half an hour.The reaction mixture again cooled to −78° C. and quenched withcyclopropyl amide 1 and stirred for two hours at −78° C. and slowlywarmed to room temperature. The reaction mixture stirred for three hoursat room temperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

[0898] Step B

[0899] To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. wasadded R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followedby addition of a solution of borane complexed with dimethyl sulfide(1.85 mL, 2M in THF). The reaction mixture was stirred for 30 minutes at0° C. and than at room temperature for one hour. The reaction mixturewas cooled to 0° C. and MeOH was added carefully. The mixture wasstirred for 20 minutes and was concentrated under reduced pressure. Theresidue was extracted with ether, washed with water, 1M HCl (10 mL),saturated sodium bicarbonate (10.0 mL) water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and removal ofsolvent afforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 13.36

[0900]

[0901] Step A

[0902] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours.After cooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

[0903] Step B

[0904] The step B alcohol was obtained following a similar procedure setforth in the preparative example 13.35 Step B.

Preparative Example 13.37

[0905]

[0906] Step A:

[0907] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silicagelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 13.38-13.45

[0908] Following a similar procedure set forth in Preparative Examples13.25 and 13.35, and using the indicated Furan and Electrophile, thefollowing Alcohols in the Table below were prepared. Prep. ex FuranElectrophile Alcohol Yield 13.38

86% 13.39

69% 13.40

84% 13.41

82% 13.42

60% 13.43

65% 13.44

82% 13.45

89%

Preparative Examples 13.50-13.61

[0909] Following a similar procedure set forth in Preparative Examples13.25, and using the indicated Alcohol, the following Amines in theTable below were prepared. PREP. EX. ALCOHOL AMINE % YIELD 13.50 13.45

28% 13.51 13.38

58% 13.52 13.36

69% 13.53 13.35

81% 13.54 13.37

82% 13.55 13.39

45% 13.56 13.41

57% 13.57 13.40

58% 13.58 13.44

54% 13.59 13.42

53% 13.60 13.43

50% 13.61 13.37

82%

Preparative Example 13.70

[0910]

[0911] Step A

[0912] The imine was prepared following the procedure set forth in thepreparative example 13.19 from the known bromoester (1.0 g) as a yellowsolid, Step A to yield 1.1 g (79%).

[0913] Step B

[0914] The Step A product (0.6 g) was reacted following the procedureset forth in the preparative example 13.19 to give the amine product0.19 g (64%).

[0915] Step C

[0916] The Step B product (1.0 g) was reacted following the procedureset forth in the preparative example 13.19 to give the acid as yellowsolid 0.9 g (94%)

[0917] Step D

[0918] The Step C product (0.35 g) was reacted following the procedureset forth in the preparative example 13.19 to give the amino acid asyellow solid 0.167 g (93%).

Preparative Example 14

[0919]

[0920] Step A

[0921] 3-Nitro-1,2-phenylenediamine (10 g), sodium nitrite (5.4 g) andacetic acid (20 mL) were heated at 60° C. overnight, then concentratedin vacuo, diluted with water and extracted with EtOAc. The productprecipitated from the organic phase (5.7 g) as a solid and used directlyin step B.

[0922] Step B

[0923] The product from Step A above (2.8 g) was stirred with 10% Pd/C(0.3 g) in MeOH (75 mL) under a hydrogen gas atmosphere overnight. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo, to give the product (2.2 g, MH+=135).

Preparative Example 15

[0924]

[0925] Step A

[0926] N-methyl-4-bromopyrazole-3-carboxylic acid was prepared accordingto known methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.;Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. 1. in Zh. Obs. Khim.(Journal of General Chemistry of the USSR) 1982, 52, 2592, and refscited therein.

[0927] Step B

[0928] To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0g), available from step A, in 65 mL of anhydrous DMF was addedbromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g),dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL)at 25° C. The mixture was stirred for 26 h, and concentrated underreduced pressure to an oily residue. This residue was treated with a 1.0M NaOH aqueous solution, and extracted with ethyl acetate (50 mL×4). Theorganic extracts were combined, washed with brine, and dried withanhydrous Na₂SO₄. Removal of solvents yielded an oil, which was purifiedby preparative thin layer chromatography, eluting with CH₂Cl₂-MeOH(20:1), to give 1.09 g of the amide product (48%, MH⁺=232.0).

[0929] Step C

[0930] To a solution of the amide (0.67 g), obtained from step B, in 8mL of concentrated sulfuric acid at 0° C. was added potassium nitrate(1.16 g) in small portions. The cooling bath was removed and the mixturewas heated at 110° C. for 6 h. After cooling to 25° C., the mixture waspoured into 80 mL of H₂O, and an additional 20 mL of H₂O was used as arinse. The aqueous mixture was extracted with CH₂Cl₂ (100 mL×4). Thecombined extracts were washed with brine (50 mL), sat. NaHCO₃ aqueoussolution (50 mL), brine (50 mL), and dried with Na₂SO₄. Evaporation ofsolvent gave an oil, which solidified on standing. The crude product waspurified by flash column chromatography, eluting with CH₂Cl₂-MeOH (1:0,50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of theproduct as a solid (MH⁺=277.1)

[0931] Step D

[0932] The product (61 mg) obtained from step C was dissolved in 3 mL ofTHF. To this solution at −78° C. was added dropwise along the insidewall of the flask a 1.6 M solution of n-butyl lithium in hexane. After45 min, a solution of methyl borate (0.1 mL) in THF (1.0 mL) was added.After 1.5 h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) wasadded to the cold mixture. Stirring was continued for 10 min, and a 30wt % aqueous hydrogen peroxide solution (0.1 mL) was added. Anadditional portion of hydrogen peroxide aqueous solution (0.05 mL) wasadded 20 min later. The cooling bath was removed, and the mixture wasstirred at 25° C. for 36 h. The mixture was poured into 30 mL of H₂O,and the aqueous mixture was extracted with ethyl acetate (30 mL×4). Theextracts were combined, washed with brine (10 mL), 5% NaHCO₃ aqueoussolution (10 mL) and brine (10 mL). The organic layer was dried withNa₂SO₄ and concentrated under reduced pressure to a residue, which wasthen purified by preparative thin layer chromatography eluting withCH₂Cl₂-MeOH (20:1) to give the hydroxylated product (5 mg, 10%,MH⁺=215.3).

[0933] Step E

[0934] By treating the hydroxylated product of Step E with H₂ under theconditions of 10% palladium on carbon in ethanol, one would obtain thedesired hydroxyl-amino compound.

Preparative Example 16

[0935]

[0936] Step A

[0937] Following a similar procedure used in Preparative Example 13,Step C except using the known compound, 4-methyl-pyrimidin-5-ol, theproduct can be prepared.

[0938] Step B

[0939] Following a similar oxidation procedure used in PreparativeExample 15, Step A except using the compound from Step A above, theproduct can be prepared.

[0940] Step C

[0941] Following a similar procedure used in Preparative Example 11,Step A except using the compound from Step B above, the product can beprepared.

[0942] Step D

[0943] Following a similar procedure used in Preparative Example 12,Step F except using the compound from Step C above, the product can beprepared.

Preparative Example 17

[0944]

[0945] Step A

[0946] Following a similar procedure used in Preparative Example 11,Step A except using the known 4-hydroxynicotinic acid, the product canbe prepared.

[0947] Step B

[0948] Following a similar procedure used in Preparative Example 13,Step C except using the compound from Step A above, the product can beprepared.

[0949] Step C

[0950] Following a similar procedure used in Preparative Example 12,Step F except using the compound from Step C above, the product can beprepared.

Preparative Example 18

[0951]

[0952] Step A

[0953] Following a similar procedure used in Preparative Example 13,Step C except using the compound from Step A above, the product can beprepared.

[0954] Step B

[0955] Stirring the compound from Step A above, a suitable Pt or Pdcatalyst and EtOH under hydrogen atmosphere (1-4 atm) the product can beprepared.

Preparative Example 19

[0956]

[0957] The product from Preparative Example 3 (14.6 g) dissolved inabsolute EtOH (100 mL) was added dropwise over 4 hours to a stirredethanolic (100 mL) solution of diethylsquarate (19 mL, 128 mmol). After5 days, the reaction mixture was concentrated in vacuo, and theresulting residue purified by column chromatography (silica gel, 0-5%MeOH/CH₂Cl₂) gave the product (65%, MH⁺=305, mp=178.6° C.).

Preparative Example 19.1

[0958]

[0959] The amine from Prepartive Example 3 (5 g) and dimethylsquarate(3.95 g) in MeOH were stirred overnight. The precipitated product wasfiltered to give 6.32 g of solid (78%, MH+=291.1)

Preparative Example 19.2

[0960]

[0961] The hydroxy thiophene amine from Preparative Example 13.34 (108mg, 0.37 mmol) was dissolved in 5 mL of ethanol and stirred withdiethoxysquarate (0.14 mL, 0.95 mmoL) and potassium carbonate (52 mg,0.38 mmol) at room temperature overnight. The mixture was diluted withH2O (25 mL), adjusted to pH˜6 using a 1.0 M HCl aqueous solution, andextracted with ethyl acetate (40 mL×3). The combined organic extractswere washed with brine, dried over Na2SO4, and concentrated to an oil,which was purified by flash column chromatography, eluting withCH2Cl2-MeOH (100:1, v/v). Removal of solvents afforded 83.5 mg of thetitled product (MH+=414).

Preparative Example 20-23.14B

[0962] Following the procedures set forth in Preparative Example 19 butusing the amine from the Preparative Example indicated in the Tablebelow, the cyclobutenedione intermediates were obtained. Amine from 1.Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 20 4

1. 85% 2. 333 21 11

1. 44% 2. 319 21.1 6

1. 9% 2. 291 22 2

1. 38% 2. 347 23 14

1. 51% 2. 259 23.1 10.1

1. 62% 2. 317 23.2 10.2

1. 61% 2. 319 23.3 12

1. 40% 2. 330 23.4 10.3

1. 42% 2. 333 23.5 10.4

1. 40% 2. 333 23.6 10.5

1. 37% 2. 347 23.7 13.2

1. 39% 2. 339 23.8 13.1

1. 42% 2. 383/385 23.9 13.19

1. 51% 2. 311 23.10 13.20

1. 67% 2. 389.1, 390 23.11 13.3

1. 52% 2. 383/385 23.12 13.21

1. 76% 2. 325.1 23.13 13.22

1. 54% 23.14 13.23

1. 62% 2. 378 23.14A 13.70 Step B

1. 60% 2. 138 23.14B 13.70 Step D

1. 65%

Preparative Example 23.15A-23.15F

[0963] Following the procedures set forth in Preparative Example 19.2but using the amines from the Preparative Example indicated in the Tablebelow, the corresponding cyclobutenedione intermediates were prepared.Amine from 1. Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 23.15A 13.29

1. 66% 2. 347 23.15B 13.30

1. 21% 2. 499 23.15C 13.31

1. 41% 2. 423 23.15D 13.32

1. 26% 2. 437 23.15E 13.33

1. 48% 2. 361.1 23.15F   13.32A

1. 68% 2. 375.1

Preparative Example 23.16-23.26

[0964] Following the procedures set forth in Preparative Example 19 butusing the amine from the Preparative Example indicated in the Tablebelow, the cyclobutenedione intermediate products were obtained. PrepAmine from Yield Ex. Prep Ex. Product (%) 23.16 13.11

91% 23.17 13.12

81% 23.18 13.17

47% 23.19 13.27

21% 23.20 13.26

10% 23.21 13.25

49% 23.22 13.13

80% 23.23 13.15

63% 23.24 13.16

64% 23.25 13.17A

48% 23.26 13.17B

66%

Preparative Example 24

[0965]

[0966] Step A

[0967] To a solution of N-protected amino acid (1.5 g, 6.9 mmol) inCH₂Cl₂ (25 mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol),and PyBrop (3.4 g, 6.9 mmol) followed by MeNH₂ (6.9 mL, 13.8 mmol, 2.0 Min CH₂Cl₂). The resulting solution was stirred for 18 h at roomtemperature (until TLC analysis deemed the reaction to be complete). Theresulting mixture was washed sequentially with 10% citric acid (3×20mL), sat. aq. NaHCO₃ (3×20 mL), and brine (3×20 mL). The organic layerwas dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The crude product was purified by flash chromatography eluting withCH₂Cl₂/MeOH (40:1) to afford 1.0 g (63% yield) of a solid.

[0968] Step B

[0969] To a round bottom charged with the N-protected amide (1.0 g, 4.35mmol) (from Step A) was added 4N HCl/dioxane (10 mL) and the mixture wasstirred at room temperature for 2 h. The mixture was diluted with Et₂O(20 mL) and concentrated under reduced pressure. The crude product wastreated with Et₂O (2×20 mL) and concentrated under reduced pressure toafford 0.72 g (˜100% yield) of crude product as the HCl salt. Thismaterial was taken on without further purification or characterization.

Preparative Examples 25-33.1

[0970] Following the procedure set forth in Preparative Example 24 butusing the commercially available N-protected amino acids and amines inthe Table below, the amine hydrochloride products were obtained. PrepEx. Amino acid Amine Product 1. Yield (%) 25

NH₃

1. 70% 26

1. 71% 27

1. 66% 28

1. 65% 29

1. 90% 30

1. 68% 31

1. 68% 32

1. 97% 33

1. 97% 33.1

1. 20%

Preparative Example 33.2

[0971]

[0972] Step A

[0973] BOC-valine (45 mg) and PS-carbodiimide (200 mg) were suspended inCH₂Cl₂ (4 ml). After addition of the CH₂Cl₂-amine solution (0.138N, 1ml), the mixture was shaken overnight. The solution was filtered and theresin was washed with more CH₂Cl₂, and the filtrate was concentrated invacuo to yield the product, which was carried on directly in Step B.

[0974] Step B

[0975] The crude material from Step A was dissolved in 4N HCl/dioxane(2.5 ml) and stirred for 2 h. The reaction was concentrated in vacuo toyield the desired amine hydrochloride, which was used directly in thenext step.

Preparative Examples 33.3-33.47

[0976] Following the procedure set forth in Example 33.2 but using thecommercially available N-protected amino acids in the Table below, theamine hydrochloride products were obtained. Prep Ex. Amino acid AmineProduct 33.3

33.4

33.5

33.6

33.7

33.8

33.9

33.10

33.11

33.12

33.13

33.14

33.15

33.16

33.17

33.18

33.19

33.20

33.21

33.22

33.23

33.24

33.25

33.26

33.27

33.28

33.29

33.30

33.31

33.32

33.33

33.34

33.35

33.36

33.37

33.38

33.39

33.40

33.41

33.42

33.43

33.44

33.45

33.46

33.47

Preparative Example 34

[0977]

[0978] To a solution of 3-chlorobenzaldehyde (2.0 g, 14.2 mmol) in THF(5 mL) at 0° C. was added LiN(TMS)₂ (17.0 ml, 1.0 M in THF) dropwise andthe resulting solution was stirred for 20 min. EtMgBr (6.0 mL, 3.0 M inEt₂O) was added dropwise and the mixture was refluxed for 24 h. Themixture was cooled to room temperature, poured into saturated aqueousNH₄Cl (50 mL), and then extracted with CH₂Cl₂ (3×50 volumes). Theorganic layers were combined, concentrated under reduced pressure. Thecrude residue was stirred with 3 M HCl (25 mL) for 30 min and theaqueous layer was extracted with CH₂Cl₂ (3×15 mL) and the organic layerswere discarded. The aqueous layer was cooled to 0° C. and treated withsolid NaOH pellets until pH=10 was attained. The aqueous layer wasextracted with CH₂Cl₂ (3×15 mL) and the organic layers were combined.The organic layer was washed with brine (1×25 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to afford 1.6 g (66% yield) of thecrude amine as an oil (MH⁺ 170). This material was determined to be>90%pure and was used without further purification.

Preparative Example 34.1

[0979]

[0980] The aldehyde (3.5 g) and conc. HCl (20 ml) were combined andstirred overnight at 40° C. The reaction mixture was poured into coldwater and extracted with ether, washed with satd. NaHCO₃ and brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give1.76 g of product (55%)

Preparative Example 34.2

[0981]

[0982] Chlorine was bubbled into 100 ml of CH₂Cl₂ at 10° C. The aldehyde(3.73 ml) was charged with 50 ml of CHCl₃ and then cooled to 0° C. AlCl₃was added portionwise, followed by the chlorine solution and let stir atroom temperature overnight. The reaction was poured into 150 ml of iceand 50 ml of 3N HCl and stirred for 30 min. Organic layer was washedwith brine, dried with Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified via flash column chromatography (Hex/EtOAc 40/1) toyield 1.5 g of pure product.

Preparative Example 34.3

[0983]

[0984] Step A

[0985] The ketone (3.25 g) was reacted following the procedure set forthin Preparative Example 88.2, Step B to give the oxime (3.5 g, 99%).

[0986] Step B

[0987] The product from step A (1.2 g) was stirred with AcOH (3 ml) andPd/C (10%, 300 mg) in EtOH (40 ml) under a hydrogen atmosphereovernight. The reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo. The crude material dissolved inether and washed with 2N NaOH, organic washed with brine, dried withNa₂SO₄, and concentrated in vacuo to give product (960 mg, 86%).

Preparative Example 34.4

[0988]

[0989] Step A

[0990] To a suspension of NaH (1.45 g) in DMF (25 ml) under a nitrogenatmosphere was added p-bromophenol (5 g) at 0° C. After stirring for 20min, BrCH₂CH(OEt)₂ (5.3 ml) was added and the reaction was heated toreflux overnight. The solution was cooled and poured into ice water (80ml) and extracted with ether. The ether layer was washed with 1N NaOHand brine, dried with MgSO₄, filtered and concentrated in vacuo to give8.4 g of crude product (100%)

[0991] Step B

[0992] To a solution of the product from Step A (8.4 g) in benzene (50ml) was added polyphosphoric acid (10 g). The mixture was heated atreflux for 4 hrs. The reaction was cooled to 0° C. and poured into icewater (80 ml) and extracted with ether. The ether layer was washed withsaturated sodium bicarbonate and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.9 g of crude product (85%)

[0993] Step C

[0994] To a solution of the product from Step B (2 g) in ether (20 ml)at −78° C. was added t-BuLi dropwise. After stirring for 20 min, DMF(950 mg) was added dropwise and the mixture was stirred at −25° C. for 3hrs and then warmed to room temperature overnight. Saturated ammoniumchloride was added and the solution was extracted with ether. The etherlayer was washed with brine, dried with MgSO₄, filtered and concentratedin vacuo to give 980 mg of crude product (67%).

[0995] Step D

[0996] To a solution of aldehyde (400 g) in ether (10 ml) was addedLiN(TMS)₂ (1M in THF, 3.3 ml) at 0° C. dropwise. The solution wasstirred at 0° C. for 30 min and EtMgBr (3M in THF, 1.83 ml) was addeddropwise. The reaction was refluxed overnight, cooed to 0° C., quenchedwith saturated ammonium chloride and extracted with ether. The ether wasstirred with 3N HCl (20 ml), then the aqueous layer was basified withNaOH pellets and extracted with ether. The ether layer was washed withbrine, dried with MgSO₄, filtered and concentrated in vacuo to give 220mg of product (46%).

Preparative Example 34.5

[0997]

[0998] Following the procedures set forth in Preparative Example 34.4Steps A through D, but using m-bromophenol (8 g), both amines wereformed and separated by preparative plate chromatography (63-65%,MH+=175).

Preparative Example 34.6

[0999]

[1000] To a solution of 3-methyl-thiophene (5 g) in ether (50 ml) wasadded dropwise a solution of n-BuLi (1.6M in hexane, 32 ml). The mixturewas stirred for 1.5 hr at room temperature. DMF (5.1 ml) was then addedand let stir overnight. The mixture was poured into saturated ammoniumchloride and extracted with ether. The ether layer was washed withbrine, dried with Na₂SO₄, and concentrated in vacuo. The crude productwas purified via flash column chromatography (EtOAc/Hex 20:1) to afford5.27 g of an oil (84%).

Preparative Example 34.7

[1001]

[1002] Step A

[1003] To a solution of 4-bromo-2-furaldehyde (4 g) in MeOH (75 ml) wasadded trimethyl-orthoformate (3.8 ml). A catalytic amount of p-toluenesulfonic acid (195 mg) and the mixture was heated to reflux for 3.5 hr.The reaction was cooled down and potassium carbonate was added. Themixture was filtered through a silica gel pad. The filtrate wasconcentrated in vacuo, dissolved in CH₂Cl₂ and filtered. The filtratewas again concentrated in vacuo to give 4.03 g of product (80%).

[1004] Step B

[1005] To a solution of the product from Step A (2.02 g) in THF (80 ml)at −78° C. was added dropwise a solution of n-BuLi (2.5M in hexanes, 4.4ml) and stirred for 1.5 hr. A solution of iodomethane (1.7 ml) was addedand let stir for 2.5 hrs at −60° C. The cooling bath was removed andsaturated ammonium chloride was added and let stir for 10 min. Thelayers were separated and the organic layer was washed with brine, driedwith Na₂SO₄, and concentrated in vacuo to afford 1.34 g of crudeproduct.

[1006] Step C

[1007] The product from Step B (1.43 g) was dissolved in acetone (50 ml)and treated with a catalytic amount of p-toluene sulfonic acid (80 mg).The mixture was heated to reflux for 2 hr. The reaction was cooled downand solid potassium carbonate was added. The mixture was filteredthrough a silica gel pad and the filtrate was concentrated in vacuo togive 1.246 g of crude product.

Preparative Example 34.8

[1008]

[1009] Step A

[1010] To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20ml) was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution ofmethyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixtureand stirred for 16 hr. Water was added and the aqueous mixture wasextracted with EtOAc. The EtOAc layer was washed with water, dried withMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 gof product (90%).

[1011] Step B

[1012] To a solution of the product from Step A (3.6 g) in toluene (16ml) was added tributyltin hydride (5.4 ml) followed by AIBN (555 mg).The mixture was heated to 85° C. for 3.5 hr. After cooling, the mixturewas separated by flash column chromatography (Hex/EtOAc, 7:1) to afford2.06 g of product (73%).

[1013] Step C

[1014] To a solution of product from Step B (2.05 g) in THF (60 ml) at0° C. was added a solution of LAH (1M in ether, 12.8 ml). The reactionwas stirred at room temperature for 30 min. Water and 1M NaOH was addeduntil a precipitate formed, diluted with EtOAc, stirred for 30 min andthen filtered through a celite pad. The organic filtrate wasconcentrated in vacuo to give 1.56 g of product (93%).

[1015] Step D

[1016] To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml)was added Dess-Martin oxidant (7.26 g) in CH₂Cl₂ (45 ml) and stirred for30 min. The mixture was diluted with ether (200 ml). The organic layerwas washed with 1N NaOH, water and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give oil and solid. The material was extractedwith ether and filtered. Some solid crystallized out from the filtrate,filtered again, and the filtrate was concentrated in vacuo to give 2.19g of product.

Preparative Example 34.9

[1017]

[1018] Step A

[1019] To a solution of carboxylic acid (5 g) in CH₂Cl₂ (400 ml) at 0°C. was added N(OCH₃)CH₃.HCl (11.5 g), DEC (15.1 g), HOBt (5.3 g) and NMM(43 ml) and stirred for 14 hr. The mixture was diluted with CH₂Cl₂ (100ml) and the organic layer was washed with 10% HCl, saturated sodiumbicarbonate and brine, dried with Na₂SO₄, and concentrated in vacuo toafford 5.74 g of crude product (85%).

[1020] Step B

[1021] To a solution of iodoethane (0.56 ml) in ether (5 ml) at −78° C.was added a solution of t-BuLi (1.7M in pentane, 8.3 ml) dropwise. Themixture was warmed to room temperature for 1 hr and transferred to a 100ml round bottom charged with the product from Step A (1 g) in THF (12ml) at −78° C. The mixture was stirred at −78° C. for 1 hr and at 0° C.for an additional 2 hr. 1M HCl was added dropwise followed by CH₂Cl₂.The layers were separated and the organic layer was washed with brine,dried with Na₂SO₄, and concentrated in vacuo to afford 620 mg of product(76%).

[1022] Step C

[1023] To a solution of the product from Step B (620 mg) in THF/MeOH(10:1) at 0° C. was added NaBH₄ (250 mg) in one portion. The mixture wasstirred overnight at 0° C., concentrated in vacuo and the crude materialwas dissolved in CH₂Cl₂ and washed with 1N NaOH and brine, dried withNa₂SO₄, and concentrated in vacuo to afford 510 mg of product.

[1024] Step D

[1025] The above material was reacted in the procedures set forth inPreparative Example 75.75 Steps B and C to yield 170 mg of amine product(28%).

Preparative Example 34.10

[1026]

[1027] The above amine was made analogous to the procedures set forth inPatent WO96/22997 p.56, but using ethylglycine instead of benzylglycinein the DCC coupling.

Preparative Example 34.11

[1028]

[1029] Step A

[1030] To the nitro compound (3.14 g) and cyclohexylmethanol (1.14 g) inTHF (50 ml) was added PPH₃ (4.72 g) and cooled to 0° C.Diisopropylazadicarboxylate (3.15 ml) was added dropwise and let stirovernight. The reaction was concentrated in vacuo and purified via flashcolumn chromatography (Hex/EtOAc, 30:1) to give product (3.3 g), whichwas carried on directly to the next step.

[1031] Step B

[1032] To the product from step A (3.3 g) in EtOH (50 ml) was added 10%Pd/C (1.7 g) under a hydrogen atmosphere at 55 psi and let stirovernight. The reaction was filtered through celite and concentrated invacuo to give 3.2 g of product.

Preparative Example 34.12

[1033]

[1034] Step A

[1035] A solution of acid (2 g) in ether (20 ml) was added dropwise to asuspension of LiAlH₄ (350 mg) in ether (15 ml) at 0° C. The solution wasrefluxed for 3 hr and stirred at room temperature ovenright. 5% KOH wasadded and reaction was filtered, extracted with ether, dried with MgSO₄,filtered and concentrated in vacuo to give the product (1.46 g, 79%,MH+=166).

[1036] Step B

[1037] To a solution of alcohol from above (1.46 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (5.6 g) portionwise and onedrop of water and let stir over the weekend at room temperature. 10%Na₂S₂O₃ was added and stirred for 20 min, extracted with CH₂Cl₂, washedwith saturated sodium bicarbonate, dried with Na₂SO₄, and concentratedin vacuo to afford 1.1 g of product (76%).

Preparative Example 34.13

[1038]

[1039] The above compound was prepared according to the procedure setforth in EP 0 555 153 A1.

Preparative Example 34.14

[1040]

[1041] The aldehyde (500 mg) from above was reacted following theprocedure set forth in the Preparative Example 13.4, Step A to yield 372mg of product (76%).

Preparative Example 34.15-34.16

[1042] Following the procedures set forth in Preparative Example 34.8but using the nitroalkanes indicated in the table below, the aldehydeswere prepared. Prep. Ex. Nitroalkane Aldehyde Yield 34.15

17% 34.16

21%

Preparative Example 34.17

[1043]

[1044] Step A

[1045] To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54mmol) in 225 mL of CH₂Cl₂ at room temperature was added oxalyl chloridefollowed by a catalytic amount of N,N′-dimethylforamide. After 1 h,ethanol (20 mL) was added followed by triethylamine (22 mL). Reactionwas continued for 15 h. The mixture was concentrated under reducedpressure to a residue, which was extracted with excess volume ofhexanes, and hexanes-CH₂Cl₂ (3:1, v/v). The extracts were filtered, thefiltrated was concentrated to a yellow oil, dried on high vacuum,yielding 17.2 g (93%) of the desired ester.

[1046] Step B

[1047] The ester product obtained from Step A above (17.2 g, 73.18 mmol)was converted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) usingthe literature procedure: J. Am. Chem. Soc., 1939, 61, 473-478.

[1048] Step C

[1049] The ester product obtained from Step B above (7.9 g, 27.13 mol)was reduced to the alcohol (6.32 g) using the procedure set forth inPreparative Example 34.8, Step C.

[1050] Step D

[1051] The product obtained from Step C above (6.32 g) was dissolved in140 mL of THF and cooled in a −78° C. bath. A 2.5 M solution ofn-butyllithium in hexanes (22 mL, 55.0 mmol) was added dropwise alongthe side wall of the flask. After 15 min, H₂O (˜70 mL) was added.Cooling bath was removed, the mixture was stirred for an additional 1 h.Brine (50 mL) and CH₂Cl₂ (300 mL) were added, the two layers wereseparated, the aqueous layer was extracted with CH₂Cl₂ (100 mL), and thecombined organic layers ere dried by Na₂SO₄. Evaporation of solventsafforded 5.33 g (crude) of the debrominated product as a reddish brownoil.

[1052] Step E

[1053] The alcohol product obtained from Step D above (5.33 g) wasoxidized to the corresponding aldehyde (3.06 g, 74% over three steps)using the procedure set forth in Preparative Example 34.8, Step D.

Preparative Example 34.18

[1054]

[1055] Step A

[1056] To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in120 mL of ether at −78° C. was added dropwise a 1.7M solution oft-butyllithium in pentane (44.5 mL, 75.7 mmol). After 10 min, coolingbath was removed, stirring was continued for 1.5 h. The mixture wascooled again in a −78° C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol)was added. Reaction was continued for 1 h, and quenched with a saturatedNH4Cl aqueous solution. The aqueous mixture was extracted with CH₂Cl₂(100 mL×3). The organic extracts were washed with brine, dried byNa₂SO₄, filtered, and concentrated in vacuo to give 5.3 g (91%) of thealcohol product as a yellow oil.

[1057] Step B

[1058] Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwiseto a vigorously stirred suspension of sodium iodide (32 g, 213.5 mmol)in 100 mL of acetonitrile. After 5 min, a solution of the alcoholobtained from Step A above (4.93 g, 35.68 mmol) in 100 mL ofacetonitrile was added dropwise. Stirring was continued for 5 min. H₂O(100 mL) was added, the layers were separated, and the aqueous layer wasextracted with ether (100 mL×2). The organic layers were combined,washed with a 10% Na₂S₂O₃ aqueous solution and brine, and dried overNa₂SO₄. Evaporation of solvents gave a dark brown oil, which wasfiltered through a 5-in silica gel column, eluting with CH₂Cl₂-hexanes(1:3.5, v/v). Removal of solvents afforded 4.22 g (47%) of the iodoproduct as a light yellow oil.

[1059] Step C

[1060] The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was addeddropwise. After 20 min, cooling bath was removed. Reaction was continuedfor 2.5 h, and quenched with H₂O (20 mL). The aqueous mixture wasstirred overnight and separated. The aqueous layer was extracted withether (30 mL). The combined organic layers were washed with brine, driedby Na₂SO₄, and filtered through a Celite pad. Removal of solvent gave1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

[1061] Step D

[1062] 3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was addeddropwise along the side wall of the flask. The mixture was stirred for 3h from −78° C. to 0° C., and continued for 1 h at room temperature. Asolution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added.Reaction was continued overnight, and quenched with a saturated NH₄Claqueous solution. The two layers were separated, the aqueous layer wasextracted with CH₂Cl₂ (30 mL×2). The combined organic layers were washedwith brine, dried with Na₂SO₄, and concentrated to an oil, which waspurified by preparative TLC (CH₂Cl₂-hexanes=1:1.5, v/v) to give 0.48 g(36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

Preparative Example 34.19

[1063]

[1064] Step A

[1065] 3-Ethylfuran was prepared from 3-hydroxymethylfuran according toliterature procedure: J. Org. Chem., 1983, 48,1106-1107.

[1066] Step B

[1067] 3-Ethylfuran obtained from Step A above was converted to4-ethyl-2-furaldehyde using the procedure set forth in PreparativeExample 34.32, Step D.

Preparative Examples 35-51.20

[1068] Following the procedure set forth in Preparative Example 34 butusing the commercially available aldehydes and Grignard reagents listedin the Table below, the amine products below were obtained. PrepGrignard 1. Yield (%) Ex. Aldehyde Reagent Amine 2. MH⁺ 35

EtMgBr

1. 65% 2. 154 36

EtMgBr

1. 75% 2. 180 37

EtMgBr

1. 78% 2. 170 38

EtMgBr

1. 34% 2. 204 39

EtMgBr

1. 68% 2. 150 40

EtMgBr

1. 40% 2. 220 41

EtMgBr

1. 73% 2. 154 42

EtMgBr

1. 52% 2. 220 43

EtMgBr

1. 55% 2. 180 44

EtMgBr

1. 20% 2. 204 45

EtMgBr

1. 80% 2. 166 46

EtMgBr

1. 35% 2. 220 47

i-PrMgBr

1. 20% 2. 150 48

EtMgBr

1. 77% 2. [M—NH₂]⁺ = 149 49

EtMgBr

1. 77% 2. 172 50

EtMgBr

1. 78% 2. [M—NH₂]⁺ = 147 51

EtLi

1. 10% 2. 116 51.2

EtMgBr

1. 37% 2. 161 51.3

EtMgBr

1. 63% 2. 216 51.4

EtMgBr

1. 71% 2. 228 51.5

EtMgBr

1. 89% 2. 168 51.6

EtMgBr

1. 20% 2. 228 51.8

EtMgBr

1. 36% 2. 222 51.10

1. 95% 2. 152.1 51.11

EtMgBr

1. 61% 2. 138.1 MH⁺—H₂O 51.12

EtMgBr

1. 70% 2. 184.1 51.18

EtMgBr

1. 42% 2. 147 [M—NH₂]⁺ 51.19

EtMgBr

1. 67% 2. 204 51.20

EtMgBr

1. 33% 2. 188

Preparative Examples 51.25-51.31

[1069] Following the procedure set forth in Example 34 but using thecommercially available aldehydes and Grignard reagents listed in theTable below, the amine products were obtained. Prep Grignard Yield Ex.Aldehyde Reagent Amine (%) 51.25

EtMgBr

20% 51.26

77% 51.27

EtMgBr

51% 51.28

56% 51.29

54% 51.30

EtMgBr

80% 51.31

10%

Preparative Example 52

[1070]

[1071] Step A

[1072] A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol),hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48-72 hrs, thenconcentrated in vacuo. The residue was diluted with EtOAc, washed with10% KH₂PO₄ and dried over Na₂SO₄ (anhydrous). Filtration andconcentration afforded the desired oxime (2.9 g, 96%) which was useddirectly in Step B without further purification.

[1073] Step B

[1074] To a mixture of the product from Step A above in TFA (20 mL) wasadded Zn powder (3 g, 3 eq) portionwise over 30 min and stirred at roomtemperature overnight. The solid was filtered and the mixture reduced invacuo. Aqueous NaOH (2 M) was added and the mixture was extractedseveral times with CH₂Cl₂. The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated to afford the desired product (1.4 g,50%).

Preparative Examples 53-61

[1075] Following the procedure set forth in Preparative Example 52 butusing the commercially available ketones listed in the Table below, thefollowing amines were obtained. Prep 1. Yield (%) Example Ketone Amine2. MH⁺ 53

1. 11% 2. 128 54

1. 33% 2. 142 55

1. 49% 2. 156 56

1. 5% 2. 154 57

1. 47% 2. 174 58

1. 71% 2. 190 59

1. 78% 2. 191 60

1. 80% 2. 190 61

1. 9% 2. 156

Preparative Example 62

[1076]

[1077] To a cooled (0-5° C.) suspension of L-α-(2-thienyl)glycine (0.5g) and LiBH₄ (2M in THF, 3.8 mL) in anhydrous THF (10 mL) was slowlyadded a THF (5 mL) solution of iodine (0.8 g). After stirring at roomtemperature for 15 min, the mixture was stirred at relux overnight.After cooling to room temperature, MeOH was added dropwise until gasevolution ceased and after 30 min, the mixture was evaporated. The oilyresidue was stirred in 20 mL KOH for 4 hrs, diluted with brine andextracted with EtOAc.

[1078] The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford a crude mixture. Purification by flashcolumn chromatography (50% EtOAc/CH₂Cl₂, silica) afforded the product(0.3 g, 63%, MH⁺=144).

Preparative Example 63

[1079]

[1080] CeCl₃—7H₂O was dried at 140-150° C. for 22 hr. To this solid wasadded THF (80 mL, anhydrous) and after stirring for 2 hr, the suspensionwas cooled to −78° C. and to it was added methyl lithium over 30 min.After stirring for an additional 30 min 2-thiophenecarbonitriledissolved in anhydrous THF (4.5 mL) was added and the resulting mixturestirred for an additional 4.5 hr at −78° C. Concentrated aqueous NH₃ (25mL) was added and the mixture was warmed to room temperature andfiltered through celite. The filtrate was extracted withdichloromethane, dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to afford a crude mixture. Purification by flash columnchromatography (5% MeOH, CH₂Cl₂, silica) afforded the desired product(1.2 g, 62%).

Preparative Example 64

[1081]

[1082] Step A

[1083] To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH₂Cl₂ (60mL) at 0° C. was added MgSO₄ (20 g) followed by dropwise addition of3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution wasstirred at 0° C. for 2 h and was allowed to warm to room temperature andstir overnight (14 h). The mixture was filtered and the drying agent waswashed with CH₂Cl₂ (2×10 mL). The filtrate was concentrated underreduced pressure to afford 8.4 g (100%) of an oil which was taken ontothe next step without further purification.

[1084] Step B

[1085] To a solution of the imine (8.4 g, 40.2 mmol) from Step A inCH₂Cl₂ (60 mL) at room temperature was added Et₃N (6.2 mL, 44.5 mmol)followed by dropwise addition of TMSCI (5.7 mL, 44.5 mmol). The mixturewas stirred for 6 h at room temperature whereupon the ppt that hadformed was filtered off and washed with CH₂Cl₂ (2×10 mL). The combinedfiltrate was concentrated under reduced pressure and was taken up inEt₂O/hexane (1:1/150 mL). The precipitate was filtered off and thefiltrate was concentrated under reduced pressure to afford 10.1 g (89%)of the protected imine as an oil. This material was taken onto the nextstep without further purification.

[1086] Step C

[1087] To a solution of Etl (4.0 g, 25.6 mmol) in Et₂O (40 mL) at −78°C. was added t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and themixture was stirred for 10 min. The mixture was warmed to roomtemperature, stirred for 1 h, and was recooled to −40° C. A solution ofthe imine (6.0 g, 21.4 mmol) from Step B in Et₂O (30 mL) was addeddropwise via addition funnel to afford a bright orange mixture. Thereaction mixture was stirred for 1.5 h at −40° C. then 3M HCl (50 mL)was added and the mixture was allowed to warm to room temperature. Water(50 mL) was added and the layers were separated. The aqueous layer wasextracted with Et₂O (2×30 mL) and the organic layers were combined anddiscarded. The aqueous layer was cooled to 0° C. and carefully treatedwith solid NaOH pellets until pH=12 was attained. The aqueous layer wasextracted with Et₂O (3×30 mL) and the combined layers were washed withbrine (1×30 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to afford 4.8 g (94% yield) of theamine as an oil. This material was taken on crude to the next stepwithout further purification.

[1088] Step D

[1089] To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80mL) at room temperature was added MeNH₂ (25 mL, 40% in water) followedby addition of a solution of H₅IO₆ (14.0 g, 61.4 mmol) in H₂O (25 mL).The heterogenous mixture was stirred for 1.5 h (until the reaction wascomplete by TLC) and the precipitate was filtered off. The resultingfiltrate was diluted with water (50 mL) and the mixture was extractedwith Et₂O (4×60 mL). The combined organic layers were concentrated to avolume of ˜30 mL whereupon 3M HCl (75 mL) was added. The mixture wasstirred overnight (12 h at room temperature) after which the mixture wasconcentrated to remove the volatiles. The aqueous layer was extractedwith Et₂O (3×40 mL) and the organic layers were discarded. The aqueouslayer was cooled to 0° C. and was carefully treated with solid NaOHpellets until pH˜12 was reached. The aqueous layer was extracted withEt₂O (3×60 mL) and the combined organic layers were dried (MgSO₄). Theorganic layer was concentrated under reduced pressure to afford 2.8 g(97% yield) of the desired amine as an oil [MH+ 154]. This compound wasproven to be>85% pure by ¹H NMR and was used crude in the subsequentcoupling step.

Preparative Examples 65-75.10J

[1090] Following the procedure set forth in Preparative Example 64 butusing the commercially available aldehydes, amino alcohols, andorganolithium reagents in the Table below, the optically pure amineproducts in the Table below were obtained. Prep Amino Organo 1. Yield(%) Ex. Aldehyde Alcohol lithium Product 2. MH⁺ 65

EtLi

1. 62% 2. 154 66

EtLi

1. 70% 2. 154 67

1. 54% 2. 166 68

1. 67% 2. 166 69

EtLi

1. 67 2. 154 70

EtLi

1. 42% 2. 142 71

EtLi

1. 36% 2. 142 72

1. 62% 2. 148 73

t-BuLi

1. 27% 2. 256 74

t-BuLi

1. 15% 2. 164 75

1. 7% 2. 204 75.1

EtLi

1. 65% 2. 123 [M—NH₂]⁺ 75.2

EtLi

1. 62% 2. 123 [M—NH₂]⁺ 75.3

EtLi

1. 93% 2. 139 [M—NH₂]⁺ 75.4

tBuLi

1. 50% 2. 167 [M—NH₂]⁺ 75.5

tBuLi

1. 48% 2. 167 [M—NH₂]⁺ 75.6

EtLi

1. 97% 2. 139 [M—NH₂]⁺ 75.7

iPrLi

1. 87 2. 153 [M—NH₂]⁺ 75.8

1. 94% 2. 151 [M—NH₂]⁺ 75.9

EtLi

1. 75% 2. 151 [M—NH₂]⁺ 75.10

tBuLi

1. 30% 2. 179 [M—NH₂]⁺ 75.10A

1. 61% 2. 135 [M—NH₂]⁺ 75.10B

EtLi

1. 24 2. 154 75.10C

EtLi

1. 32% 2. 165 [M—NH₂]⁺ 75.10D

MeLi

1. 47% 2. 137 [M—NH₂]⁺ 75.10E

iPrLi

1. 30% 2. 165 [M—NH₂]⁺ 75.10F

1. 67% 2. 163.0 [M—NH₂]⁺ 75.10G

EtLi

1. 24% 2. 165 [M—NH₂]⁺ 75.10H

EtLi

1. 70% 2. 194 75.10J

EtLi

1. 54% 2. 208

Preparative Examples 75.11-75.59

[1091] Following the procedure set forth in Preparative Example 64 butusing the prepared or commercially available aldehydes, amino alcohols,and organolithium reagents in the Table below and carrying the amine oncrude, the optically pure amine products in the Table below wereobtained. Prep Amino Organo Yield Ex. Aldehyde Alcohol lithium Product(%) 75.11

52% 75.12

50% 75.13

iPrLi

57% 75.14

iPrLi

54% 75.15

iPrLi

58% 75.16

61% 75.17

EtLi

72% 75.18

68% 75.19

iPrLi

77% 75.20

t-BuLi

15% 75.21

MeLi

50% 75.22

EtLi

23% 75.24

EtLi

20% 75.27

EtLi

65% 75.28

iPrLi

61% 75.29

EtLi

90% 75.30

iPrLi

62% 75.31

iPrLi

43% 75.32

50% 75.33

50% 75.34

tBuLi

51% 75.35

MeLi

51% 75.36

tBuLi

57% 75.37

tBuLi

60% 75.38

EtLi

73% 75.39

MeLi

48% 75.41

52% 75.42

EtLi

40% 75.43

tBuLi

20% 75.44

t-BuLi

79% 75.45

iPrLi

55% 75.46

tBuLi

39% 75.47

iPrLi

55% 75.48

34% 75.49

EtLi

61% 75.50

tBuLi

25% 75.51

iPrLi

33% 75.52

tBuLi

30% 75.53

EtLi

39% 75.54

38% 75.55

EtLi

64% 75.56

EtLi

46% 75.57

EtLi

62% 75.58

iPrLi

24% 75.59

EtLi

70%

Preparative Example 75.75

[1092]

[1093] Step A

[1094] To a solution of aldehyde (2.5 g) in ether (50 ml) at 0° C. wasadded EtMgBr (4.56 ml) dropwise. The heterogenous mixture was stirredfor 2 hr at 0° C. and then poured into a beaker of saturated ammoniumchloride (25 ml), ice and CH₂Cl₂ (30 ml). After the biphasic mixturestirred for 10 min, the organic layer was separated, washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo to afford theproduct (2.41 g, 95%)

[1095] Step B

[1096] To a solution of alcohol from Step A above (1 g) in toluene atroom temperature was added DPPA. The mixture was cooled to 0° C. and DBUwas added and let stir for 12 hr at room temperature. The layers wereseparated and the organic layer was washed with water, 1N HCl and driedover Na₂SO₄, filtered, and concentrated in vacuo. Purified bypreparative plate chromatography (hexane/EtOAc 20/1) to give the product(840 mg, 75%).

[1097] Step C

[1098] To a solution of azide (730 mg) from Step B above in THF (7 ml)was added PPh₃ (1 g). The heterogenous solution was stirred for 12 hr,whereupon water (1.5 ml) was added. The mixture was refluxed overnight,cooled to room temperature and concentrated in vacuo. Ether and 1N HClwere added to the residue. The aqueous layer was cooled to 0° C.,basified with NaOH pellets and extracted with ether. The ether layer wasdried over MgSO₄, filtered, and concentrated in vacuo to afford theproduct (405 mg, 62%).

[1099] Step D

[1100] To a solution of azide in THF at −10° C. was added LiAIH₄portionwise. The heterogenous solution was stirred at room temperaturefor 1 hr and then refluxed for 4 hr. The solution was cooled to 0° C.and water, 2M NaOH and ether were added to the reaction. The mixture wasfiltered through a celite pad. The filtrate was treated with 3N HCl. Theaqueous layer was cooled to 0° C., basified with NaOH pellots andextracted with ether. The ether layer was dried over MgSO₄, filtered,and concentrated in vacuo to afford the product.

Preparative Example 75.76-75.90

[1101] Following a similar procedure set forth in Preparative Example75.75, and using the reduction procedure indicated, the following amineswere obtained. Prep Reducing Ex. Aldehyde Step Product % Yield 75.76

D

43% 75.77

C

36% 75.78

D

32% 75.79

C

42% 75.80

D

56% 75.81

D

35% 75.82

C

13% 75.83

C

42% 75.84

C

39% 75.85

C

26% 75.86

C

25% 75.87

C

14% 75.88 (34.14)

C

49% 75.89 (34.13)

C

34% 75.90

C

44%

Preparative Example 76

[1102]

[1103] The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 76.1

[1104]

[1105] Step A

[1106] To a solution of amine from Preparative Example 75.90 (2.22 g) inCH₂Cl₂ (50 ml) at 0° C. was added TEA (3.03 ml) followed by BOC₂O (2.85g). The heterogenous mixture was allowed to stir at room temperatureovernight. 10% Citric acid was added to the reaction and the layers wereseparated. The organic layer was washed with saturated sodiumbicarbonate, brine and dried with Na₂SO₄, filtered, and concentrated invacuo. The crude material was purified by flash column chromatography(Hex/EtOAc 10:1) to afford 2.7 g of an oil (81%).

[1107] Step B

[1108] Following the procedure from Preparative Example 13.4, Step A,but using the product from Step A above (450 mg) and 3-thiophene boronicacid (284 mg), the product was prepared (325 mg, 71%).

[1109] Step C

[1110] To the product from Step B (325 g) was added 4M HCl in dioxane(1.31 ml) and let stir for 1 hr. The reaction was concentrated in vacuoand taken up in CH₂Cl₂ and concentrated in vacuo again. This procedurewas repeated 5 times to afford a semisolid (89%).

Preparative Example 76.2-76.3

[1111] Following the procedures set forth in Preparative Example 76.1,but using the commercially available boronic acids, the indicated amineswere prepared. Prep Ex. Boronic Acid Product Yield (%) 76.2

70% 76.3

35%

Preparative Example 76.10

[1112]

[1113] Step A

[1114] The product from Preparative Example 75.75, Step A (2.5 g) wasreacted via the Preparative Example 13.11, Step B to give the ketone(1.93 g, 78%).

[1115] Step B

[1116] To a solution of ketone from Step A above (500 mg) in THF (5 ml)at 0° C. was added S-2-methyl-CBS-oxazaborolidine (0.98 ml) dropwisefollowed by BH₃.Me₂S (1.48 ml). The mixture was stirred at 0° C. for 2hr and was allowed to warm to room temperature and stir overnight. Themixture was cooled to 0° C. and treated with is MeOH (10 ml). Afterstirring for 20 min, the reaction was concentrated in vacuo. The residuewas dissolved in CH₂Cl₂ and washed with 1M HCl, saturated sodiumbicarbonate, water and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified by preparativeplate chromatography (Hex/EtOAc 4:1) to afford 650 mg of an oil (89%).

[1117] Step C

[1118] The chiral alcohol from Step B above was reacted via thePreparative Example 75.75 Step B to give the azide.

[1119] Step D

[1120] The azide from Step C above was reacted via the PreparativeExample 75.75 Step C to give the amine product.

Preparative Example 76.11

[1121]

[1122] The desired compound was prepared as in Preparative Example76.10, but using the R-2-methyl-CBS-oxazaborolidine in step B.

Preparative Example 77

[1123]

[1124] The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 78

[1125]

[1126] The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39,181-183.

Preparative Example 78.1

[1127]

[1128] The desired compound was prepared according to methods previouslydescribed in J. Organometallic Chem. 1998, 567, 31-37.

Preparative Example 79

[1129]

[1130] The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39, 181-183.

Preparative Example 80

[1131]

[1132] The desired compound was prepared according to methods previouslydescribed in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 andc) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 81

[1133]

[1134] The desired compound was prepared according to methods previouslydescribed in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 andc) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 82

[1135]

[1136] The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1988, 31, 2176-2186.

Preparative Example 83

[1137]

[1138] To a solution of carboxylic acid (1.5 g, 7.89 mmol) inH₂O/acetone (1:10/12 mL total) at 0° C. was added Et₃N (1.43 mL, 10.3mmol) followed by addition of ethyl chloroformate (0.83 mL, 8.68 mmol).The resulting mixture was stirred for 30 min after which a solution ofNaN₃ (0.77 g, 11.8 mmol) in H₂O (2 mL) was added dropwise. The resultantheterogenous mixture was stirred for 1 h at 0° C., then cold water (5mL) and Et₂O (10 mL) were added. The layers were separated and theaqueous layer was extracted with Et₂O (2×10 mL). The organic layers werecombined, toluene (20 mL) was added, and the organic layers were dried(MgSO₄) and concentrated under reduced pressure to a volume of 20 mL.t-BuOH (5 mL) was added and the mixture was refluxed for 12 h. Themixture was concentrated under reduced pressure and the crude residuewas taken up in 3M HCl (30 mL) and was heated at reflux for 12 h. Themixture was cooled to room temperature and extracted with Et₂O (3×15mL). The aqueous layer was cooled to 0° C. and solid NaOH pellets wereadded until pH˜12 was reached. The aqueous layer was extracted with Et₂O(3×30 mL) and the combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to afford 0.78 g (61% yield) of anoil [MH⁺ 162]. This material was used without further purification.

Preparative Example 84

[1139]

[1140] The corresponding cyclopropyl analog was prepared according tothe procedure outlined in Preparative Example 83.

Preparative Example 85

[1141]

[1142] The corresponding cyclohexyl analog was prepared according to theprocedure outlined in Preparative Example 83.

Preparative Example 86

[1143]

[1144] The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1978, 43, 892-898.

Preparative Example 87

[1145]

[1146] A mixture of (R)-(+)phenylpropanolamine (8.2 g),3,4-diethoxy-3-cyclobutene-1,2-dione (10 g) and absolute EtOH (75 mL)was stirred at 0-25° C. for 12 hrs. Filtration and concentration of thefiltrate gave a syrup which was chilled in the freezer to give a solid.Trituration of the solid with diethyl ether gave the desired product(10.5 g, 71%, MH⁺=260).

Preparative Example 87.1

[1147]

[1148] (R)-1-phenyl propylamine (4.82 ml) and3,4-dimethoxy-3-cylclobutene-1,2-dione (5.03 g) were combined in MeOH(40 ml) and stirred overnight. Reaction concentrated in vacuo andpurified via flash column chromatography (MeOH/CH₂Cl₂, 1:40) to yield2.75 g of product (31%, MH+=246).

Preparative Example 88

[1149]

[1150] A mixture of (S)-(+)-3-methyl-2-butylamine (3.0 g),3,4-diethoxy-3-cyclobutene-1,2-dione (5 g) and absolute EtOH (100 mL)was stirred at 0-25° C. for 12 hrs. Filtration and concentration of thefiltrate gave a syrup which solidified upon dilution with Et₂O.Trituration of the solid with diethyl ether gave the desired product asa solid (4.4 g, 72%, MH⁺=212).

Preparative Example 88.1

[1151]

[1152] A mixture of amine from Preparative Example 75.1 (370 mg),3,4-diethoxy-3-cyclobutene-1,2-dione (0.39 ml) and absolute EtOH (5 ml)was stirred at room temperature overnight. Purification by preparativeplate chromatography (3% EtOH/CH₂Cl₂) afforded the desired product (263mg, 37%).

Preparative Example 88.2

[1153]

[1154] Step A

[1155] 2-Methylthiophene (3 g) was dissolved in THF and cooled to 40° C.N-butyllithium (2.5M in hexane, 12.24 ml) added dropwise and let stir at−40° C. for 30 min. CuBr.(CH₃)₂S (6.29 g) added and let warm to −25° C.where the trifluoroaceticanhydride (4.32 ml) was added. The reaction wasstirred at −15° C. over the weekend. The reaction was quenched withsaturated ammonium chloride and extracted with EtOAc. The organic layerwashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 4.59 g of an oil (78%).

[1156] Step B

[1157] The product from Step A (4.58 g), hydroxylamine hydrochloride (3g), sodium acetate (4.4 g), EtOH (75 ml) and H₂O (7.5 ml) were combinedand heated to 75° C. overnight. The reaction was concentrated in vacuo ,taken up 1N HCl, extracted with ether, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

[1158] Step C

[1159] The product from Step B above (4.5 g) was dissolved in TFA (40ml) and cooled to 0° C. Zn powder (4.2 g) was added portionwise and letreaction warm to room temperature and stir overnight. The reaction wasconcentrated in vacuo, taken up in 1N NaOH, extracted with ether, driedwith MgSO₄, filtered and concentrated in vacuo to give 3.43 g of theproduct (80%).

[1160] Step D

[1161] The product from Step C (526 mg),3,4-diethoxy-3-cyclobutene-1,2-dione (0.4 ml) and absolute EtOH (10 ml)was stirred at room temperature overnight. Purification by preparativeplate chromatography (10% EtOAc/Hex) to give 178 mg of product (21%,MH+=320).

Preparative Example 88.3

[1162]

[1163] Following a similar procedure as described in Preparative Example88.2, but instead using 2-methylfuran, the above cyclobutenedioneintermediate was prepared.

Preparative Example 88.4

[1164]

[1165] The amine from Preparative Example 75.1 (973 mg) and thedimethoxysquarate (870 mg) were dissolved in MeOH (20 ml) and stirredfor 3 days. The reaction was concentrated in vacuo and purified viaflash column chromatography (MeOH/CH₂Cl₂, 1%) to yield 325 mg of product(19%, MH+=249.8).

Preparative Example 88.5

[1166]

[1167] The amine from Preparative Example 75.9 (323 mg) and thedimethoxysquarate (426 mg) were dissolved in MeOH (10 ml) and stirredover the weekend. The reaction was concentrated in vacuo and purifiedvia flash column chromatography (MeOH/CH₂Cl₂, 1:20) to yield 407 mg ofproduct (57%, MH+=235.8).

Preparative Example 89

[1168]

[1169] To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at roomtemperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwiseto afford a heterogenous reaction mixture. The mixture was allowed tostand overnight (12 h) and MeI (0.32 mL, 5.1 mmol) was added dropwise.The mixture was stirred for 6 h after which the mixture was carefullypoured into cold brine (125 mL). The mixture was extracted with Et₂O(3×25 mL) and the organic layers were combined. The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford the crude product as an oil. This material was carried on crudeto the coupling step without further purification or characterization.

Preparative Example 89.1

[1170]

[1171] To a solution of KH (1.1 g) in THF (20 ml) at room temperaturewas added (R)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenousmixture. The mixture was allowed to stand overnight (18 hr) and then MeI(1.59 ml) was added dropwise. The mixture was stirred for 4 hr afterwhich brine was added. Extracted with ether, dried with K₂CO₃, filteredand concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 89.2

[1172]

[1173] To a solution of KH (1.1 g) in THF (20 ml) at room temperaturewas added (S)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenousmixture. The mixture was allowed to stand overnight (18 hr) and then MeI(1.59 ml) was added dropwise. The mixture was stirred for 4 hr afterwhich brine was added. Extracted with ether, dried with K₂CO₃, filteredand concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 90

[1174]

[1175] The corresponding cis analog was prepared in an analogous fashionutilizing the procedure described in Preparative Example 89. Thismaterial was also used without further purification.

Preparative Example 91

[1176]

[1177] The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1987, 52, 4437-4444.

Preparative Example 92

[1178]

[1179] The desired compound was prepared according to methods previouslydescribed in Bull. Chem. Soc. Jpn. 1962, 35, 11-16.

Preparative Example 93

[1180]

[1181] The desired amine was prepared from the corresponding ketoneaccording to standard methods previously described in a) Synthesis 1987,998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34,2176-2186.

Preparative Example 94

[1182]

[1183] The desired amine was prepared from the corresponding ketoneaccording to standard methods previously described in a) Synthesis 1987,998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34,2176-2186.

Preparative Example 95

[1184]

[1185] Step A

[1186] Lithium hexamethyldisilylazide (34 mL, 1M in THF) was addeddropwise to a −78° C. THF (20 mL) solution of isobutyronitrile (2.8 mL).After 40 min, cyclopropylmethylbromide (5 g) was added and the mixturewarmed to and stirred at 25° C. overnight. After cooling to 0° C., 1MHCl (aq) was added and the mixture was extracted with diethyl ether,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo at 0° C.to give the desired product (4.5 g).

[1187] Step B

[1188] Methyl Lithium (17 mL, 1.4 M in Et₂O) was added to the productfrom Step A above (1.5 g) in Et₂O (anhydrous) at 0° C. The mixture wasstirred at 0-25° C. overnight, then diluted with 3M HCl (aq), extractedwith CH₂Cl₂, dried over anhydrous Na₂SO₄, filtered, concentrated invacuo at 0° C. and used directly in Step C.

[1189] Step C

[1190] The product from Step B above was added to a slurry of NaBH₄ (1.4g) in isopropanol (50 mL) at 0° C., then the mixture was stirred atreflux for 8 hr and at room temperature for 48 hrs. Water was added andthe mixture was stirred for 30 min, then extracted with diethyl ether,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was diluted with CH₂Cl₂ and extracted with 3M HCl. The organicphase was discarded and the aqueous phase was basified with NaOH (aq)and extracted with CH₂Cl₂. Drying over anhydrous Na₂SO₄, filtering, andconcentration in vacuo gave the desired compound (0.5 g).

Preparative Example 96

[1191]

[1192] Step A

[1193] 2-Thiophenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in100 mL dichloromethane. After addition of diisopropylethylamine (4.1 mL,23.4 mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture wasstirred for 4 h at room temperature. The resulting mixture was put intowater (500 mL) and acidified with 3N HCl to pH˜1. Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in the next step without anyfurther purification. ¹H NMR (300 MHz, d₆-DMSO) 1.60 (s, 9H), 3.29 (dd,4H), 3.69 (dd, 4H), 7.23 (dd, 1H), 7.49 (d, 1 H), 7.79 (d, 1H).

[1194] Step B

[1195] The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H),7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

[1196] Step C

[1197] The crude material (3.50 g, 17.8 mmol) from Step B was dissolvedin dichloromethane (100 mL). After addition of diisopropylethylamine(18.7 mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), andPyBrOP (10.4 g, 22.3 mmol), the resulting mixture was stirred over nightat room temperature before being put into 1N sodium hydroxide (200 mL).Extraction with dichloromethane (2×200 mL) removed all PyBrOPby-products. The aqueous phase was acidified with 3N HCl andsubsequently extracted with dichloromethane (3×100 mL). The combinedorganic phases of the acidic extraction were dried over sodium sulfate,concentrated, and finally purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (2.31 g,34% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H),7.10-8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

[1198] Step D

[1199] The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved inmethanol (50 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (1.78 g,84%). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H), 7.22 (m, 2H), 7.55(d, 1H), 7.71 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 10.85 (bs, 1H).

Preparative Example 97

[1200]

[1201] Step A

[1202] Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl₂ (15 mL).After addition of dimethylformamide (5 drops), the reaction mixture wasstirred for 4 hours. Evaporation of the solvent yielded thecorresponding acid chloride as HCl-salt. Without any furtherpurification, the solid was suspended in 120 mL dichloromethane. Afteraddition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piparazine(4.8 g, 25.5 mmol), the reaction was stirred over night at roomtemperature. The resulting mixture was put into water (500 mL) andextracted with dichloromethane (2×100 mL). Drying over sodium sulfateresulted in sufficiently pure product that was used in Step B withoutany further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.63 (s, 9H), 3.21(dd, 4H), 3.61 (dd, 4H), 7.57 (dd, 1H), 7.63 (d, 1H), 7.98 (dd, 1H),8.70 (d, 1H).

[1203] Step B

[1204] The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 days, thereaction mixture was put into 1N sodium hydroxide (400 mL). Extractionwith dichloromethane (2>100 mL) and drying over sodium sulfate resultedin sufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.77 (dd, 2H), 2.83 (dd, 1H),3.38 (dd, 2H), 3.64 (dd, 1H), 7.58 (dd, 1H), 7.62 (d, 1H), 8.00 (dd,1H), 8.67 (d, 1H).

[1205] Step C

[1206] The crude material (1.35 g, 7.06 mmol) from Step B was dissolvedin dichloromethane (50 mL). After addition of diisopropylethylamine (3.7mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP(3.62 g, 7.77 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed any PyBrOP products.The aqueous phase was acidified with 3N HCl. Adjustment of the pH withsaturated sodium carbonate solution to almost neutral crushed thedesired compound out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.35 g,16% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.95 (m, 8H), 7.22 (m,1H), 7.61 (m, 1H), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m,1H), 10.82 (s, 1H).

[1207] Step D

[1208] The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolvedin methanol (60 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.10 g,89%). ¹H NMR (300 MHz, d₆-DMSO) 3.50-3.85 (m, 8H), 6.47 (dd 1H), 6.74(m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 98

[1209]

[1210] Step A

[1211] 1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) wasdissolved in dichloromethane (50 mL). After addition of PyBrOP (16.3g.35.0 mmol), diisopropylethylamine (14.0 mL, 73.0 mmol) andBoc-piparazine (5.5 g, 30.0 mmol), the reaction was stirred over nightat room temperature before being put into 1N sodium hydroxide (200 mL).Extraction with dichloromethane (2×100 ml ) removed all PyBrOPby-products. The aqueous phase was acidified with 3N HCl. Adjustment ofthe pH with saturated sodium carbonate solution to almost neutralprecipitated the desired compound. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 mL). The combined organic phasesof the neutral extraction were dried over sodium sulfate. Removal of thesolvent resulted in sufficiently pure product that was used in Step Bwithout any further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.59 (s, 9H)3.21 (dd, 4H), 3.61 (dd, 4H), 3.74 (s, 3H), 6.11 (dd, 1H), 6.33 (d, 1H),7.01 (d, 1H).

[1212] Step B

[1213] The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 3 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (3×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.79 (dd, 4H), 3.62 (dd, 4H),3.76 (s, 3H), 6.11 (dd, 1H), 6.37 (d, 1H), 6.96 (d, 1H).

[1214] Step C

[1215] The crude material (3.15 g, 16.3 mmol) from Step B was dissolvedin dichloromethane (100 mL). After addition of diisopropylethylamine(8.5 mL, 49.0 mmol), 3-nitrosalicylic acid (3.13 g, 17.1 mmol), andPyBrOP (9.11 g, 19.6 mmol), the resulting mixture was stirred over nightat room temperature before being put into 1N sodium hydroxide (400 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified with 3N HCl until thecolor of the solution changes from orange to yellow and the desiredcompound crashed out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 ml). The combined organic layersof the acidic extraction were dried over sodium sulfate and concentratedin vacuo to yield the desired product. ¹H NMR (300 MHz, d₆-DMSO)3.35-3.85 (m, 8H), 3.79 (s, 3H), 6.13 (dd, 1H), 6.45 (d, 1H), 7.01 (s,1H), 7.22 (dd, 1H), 7.70 (d, 1H), 8.16 (d, 1H), 10.83 (s, 2H).

[1216] Step D

[1217] The crude nitro-compound from Step C was suspended in methanol(60 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through Celite and washedthoroughly with methanol. The filtrate was concentrated in vacuo andpurified by column chromatography (dichloromethane/methanol=10/1) toyield the desired product (2.61 g, 40% for 4 steps). ¹H NMR (300 MHz,d₆-DMSO) 3.45-4.80 (m, 8H), 3.79 (s, 3H), 6.17 (dd, 1H), 6.45 (m, 2H),6.78 (m, 2H), 7.01 (d, 1H).

Preparative Example 99

[1218]

[1219] Step A

[1220] 2-Bromopyridine N-oxide hydrochloride (1.13 g, 5.37 mmol) andBoc-piperazine (1.50 g, 8.06 mmol) were heated to 80° C. in pyridine (10mL) over night. The reaction mixture was put into water (300 mL) andthen extracted with dichloromethane (2×100 mL). The combined organicphases were dried over sodium sulfate, concentrated, and finallypurified by column chromatography (dichloromethane/methanol=10/1) toyield the desired product (500 mg, 33%). ¹H NMR (300 MHz, d-CDCl₃) 1.60(s, 9H), 3.46 (dd, 4H), 3.78 (dd, 4H), 6.99 (m, 2H), 7.37 (dd, 1H), 8.33(d, 1H).

[1221] Step B

[1222] The purified product (500 mg, 1.79 mmol) was stirred for 30 minwith 4N HCl/dioxane (15 mL). Evaporation of the solvent yielded thecrude amine (465 mg) as multiple HCl-salt which was used in Step Cwithout any further purification. ¹H NMR (300 MHz, d₆-DMSO) 3.38 (m,4H), 4.81 (m, 4H), 7.34 (dd, 1H), 7.55 (d, 1H), 7.86 (dd, 1H), 8.55 (d,1H).

[1223] Step C

[1224] The crude material (370 mg, 1.48 mmol) from Step B was suspendedin dichloromethane (20 mL). After addition of diisopropylethylamine (2.6mL, 14.8 mmol), 3-nitrosalicylic acid (406 mg, 2.22 mmol), and PyBrOP(1.21 g, 2.59 mmol), the mixture was stirred over night at roomtemperature before being put into 1N sodium hydroxide (50 mL).Extraction with dichloromethane (2×50 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified (pH˜4-5) with 3N HCl andextracted with dichloromethane (3×50 mL). The combined organic layers ofthe acidic extraction were dried over sodium sulfate, concentrated invacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (330 mg,65%).

[1225] LCMS calculated: 344.1, found: (M+1)⁺ 345.1

[1226] Step D

[1227] Sodium hydrosulfite (1.05 g) was dissolved in water (3.0 mL) toyield a 1.5N solution. Addition of dioxane (3.0 mL) was followed byinjection of conc. ammonium hydroxide (0.60 mL, yields a 1.0Nconcentration). After addition of the nitro-compound (100 mg, 0.29mmol), the reaction mixture was stirred for 0.5 h. Subsequently, thesolvent was removed and the residue suspended indichloromethane/methanol (10/1). Filtration through Celite removed mostof the salts. Final purification by column chromatography(dichloromethane/methanol=5/1) yielded the desired product (68 mg, 75%).

[1228] LCMS calculated: 314.14, found: (M+1)⁺ 315.1

Preparative Example 100

[1229]

[1230] Step A

[1231] 4-Bromopyridine hydrochloride (3.0 g, 15.4 mmol) was dissolved inwater (15 mL). After addition of N-benzylpiperazine (14.8 mL, 85.0 mmol)and 500 mg copper sulfate, the reaction mixture was heated overnight to140° C. The resulting product was extracted with ether (5×75 mL), driedover sodium sulfate and concentrated. Final purification by columnchromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) yielded thedesired product (2.16 g, 55%). ¹H NMR (300 MHz, d-CDCl₃) 2.68 (dd, 4H),3.45 (dd, 4H), 6.76 (d, 2H), 7.40 (m, 5H), 8.38 (d, 2H).

[1232] Step B

[1233] The benzylamine (2.16 g, 8.54 mmol) from Step A, ammonium formate(2.71 g, 43.0 mmol) and Pd(C) (10%, 1.0 g) was suspended in methanol (50mL) and refluxed for 3 h. The palladium was filtered off and thefiltrate was concentrated. The sufficiently pure product was used inStep C without any further purification. ¹H NMR (300 MHz, d-CDCl₃) 2.48(bs, 1H), 3.13 (dd, 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H).

[1234] Step C

[1235] The crude material (1.15 g, 7.06 mmol) from Step B was dissolvedin dichloromethane (50 mL). After addition of diisopropylethylamine (4.7mL, 42.4 mmol), 3-nitrosalicylic acid (1.94 g, 10.6 mmol), and PyBrOP(5.78 g, 12.3 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was carefully acidified to pH˜5-6 with 3N HCl andextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(850 mg, 37% for 2 steps).

[1236] Step D

[1237] The nitro-compound (850 mg, 2.59 mmol) from Step C was dissolvedin methanol (40 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(650 g, 84%). ¹H NMR (300 MHz, d₆-DMSO) 3.40-3.75 (bm, 8H), 6.49 (dd,1H), 6.76 (m, 2H), 6.93 (d, 2H), 8.28 (d, 2H).

Preparative Example 101

[1238]

[1239] Step 1

[1240] N,N′-Dibenzyl-ethane-1,2-diamine (20 mL, 0.0813 mol),triethylamine (22.66 mL, 0.1626 mol) and benzene (100 mL) were combinedin a round bottom flask. A solution of 2,3-dibromo-propionic acid ethylester (11.82 mL, 0.0813 mol) in benzene (50 mL) was added dropwise. Thesolution was refluxed over night and monitored by TLC (20% ethylacetate/hexane). The reaction was cooled to room temperature, thenfiltered and washed with benzene. The filtrate was concentrated thenpurified by column chromatography (15% ethyl acetate/hexane). Theproduct was isolated as an oil (25.42 g, 0.0752 mol, 92%). MS:calculated: 338.20, found: 339.2

[1241]¹H NMR (300 MHz, CDCl₃) 1.23 (t, 3H), 2.48 (m, 3H), 2.62 (m, 1H),2.73 (m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.42 (d, 1H), 3.56 (m, 2H),3.91 (d, 1H), 4.17 (m, 2H), 7.27 (m, 10H).

[1242] Step 2

[1243] In a Parr shaker vessel, the ester (25.43 g, 0.075 mol) andmethanol (125 mL) were combined. The vessel was purged with argon andpalladium catalyst (5% on carbon, 2.5 g) was added. The system wasshaken under an atmosphere of hydrogen overnight. TLC (20% ethylacetate/hexane) indicated that reaction was complete. The reactionmixture was filtered through a pad of Celite and washed with methanol.The filtrate was concentrated and the product isolated as a solid (11.7g, 0.074 mol, 98%).

[1244] MS: calculated: 158.11 , found:159.2 ¹H NMR (300 MHz, CDCl₃) 1.27(t, 3H), 2.70 (m, 4H), 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd, 1H), 4.18(m, 2H).

Preparative Example 102

[1245]

[1246] Piperazine-2-carboxylic acid ethyl ester (3.11 g, 0.0197 mol),diisopropylethylamine (5.15 mL, 0.0296 mol) and methylene chloride (200mL) were combined in a round bottom flask. While stirring at roomtemperature, a solution of N,N-dimethylcarbamoyl chloride (1.81 mL,0.0197 mol) in methylene chloride (20 mL) was added dropwise. Thereaction was stirred for one hour. After this time the reaction wasconcentrated and carried on to the next step without furtherpurification. (99% yield).

[1247] MS: calculated: 229.14, found: 230.1

[1248]¹H NMR (300 MHz, CDCl₃) 1.30 (t, 3H), 2.85 (s, 6H), 3.10 (m, 3H),3.31 (m, 2H), 3.60 (m, 2H), 4.21 (q, 2H).

Preparative Example 103-104

[1249] Following the procedure described for Example 102, the Productslisted in the table below were prepared using the commercially availablechloride shown and piperazine-2-carboxylic acid ethyl ester fromPreparative Example 101. 1. Yield (%) Example Chloride Product 2. (M +1)⁺ 103

1. 99% 2. 237.1 104

1. 62% 2. 253.1

Preparative Example 105

[1250]

[1251] Step 1

[1252] 3-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099mol) and ethyl acetate (130 mL) were combined in a round bottom flaskand stirred for 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acidethyl ester (4.51 g, 0.0197 g) was added, and the reaction was stirredfor 72 hours. The reaction mixture was concentrated then dissolved indichloromethane. The organic phase was washed once with 0.1N sodiumhydroxide. The aqueous phase was back extracted once withdichloromethane. The aqueous phase was acidified and wash three timeswith ethyl acetate. The aqueous phase was concentrated and purified bycolumn chromatography (5% methanol/DCM).

[1253] MS: calculated: 394.15, found: 395.0

[1254]¹H NMR (300 MHz, CDCl₃) 1.32 (t, 3H), 2.86 (m, 7H), 3.15 (m, 1H),3.51 (m, 4H), 4.24 (m, 3H), 7.15 (m, 1H), 7.66 (m, 1H), 8.20 (m, 1H),10.86 (bs, 1H).

[1255] Step 2

[1256]4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylicacid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combinedin a round bottom flask. The system was purged with argon. To thesolution was added 5% palladium on carbon (˜100 mg). The flask waspurged with hydrogen and stirred overnight. The reaction was filteredthrough a pad of celite and washed with methanol. The material wasconcentrated then purified by column chromatography (6% methanol/DCM).Isolated product (0.74 g, 0.002 mol, 100%).

[1257] MS: calculated: 364.17, found: 365.1

[1258]¹H NMR (300 MHz, CDCl₃) 1.27 (t, 3H), 2.85 (m, 8H), 3.18 (1H),3.45 (m, 3H), 4.19 (m, 3H), 3.90 (m, 3H)

[1259] Step 3

[1260]1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylicacid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution ofdioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 0.006 mol)was added and the mixture stirred for two hours. The solution wasacidified to pH=6 with 3N HCl then extracted with butanol. The extractswere combined, dried over sodium sulfate and concentrated.

[1261] MS: calculated: 336.14, found: 337.1

[1262]¹H NMR (300 MHz, CD₃OD) 2.86 (m, 7H), 3.23 (m, 3H), 3.54 (m, 3H),6.92 (m, 2H), 7.23 (m, 1H).

Preparative Example 106-107

[1263] Following the procedure described for Example 105, the Productslisted in the table below were prepared using the amine from thePreparative Example indicated and 3-nitrosalacylic acid. 1. Yield (%) 2.(M + 1)⁺ Example Aniline Product 3. Note 106 103

1. 91% 2. Not observed 3. Rainey nickel used in Step 2 107 104

1. 24% 2. 360.0 3. For Step 1 used PyBrop/ DIEA in DCM

Preparative Example 108

[1264]

[1265] Step A

[1266] 3-Nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethylacetate (20 mL). 1,3-Dicyclohexylcarbodiimide (0.568 g, 2.8 mmol) wasadded and the mixture was stirred for approximately 10 minutes andcooled to 0° C. During this time a precipitate formed. Azetidine (0.39mL, 5.8 mmol) was added and the reaction was stirred overnight andallowed to warm to room temperature. After this time the reaction wascooled to 0° C. and filtered. The collected solid was washed withchilled ethyl acetate. The filtrate was concentrated and purified bycolumn chromatography (80% EtOAc/Hex) to give the product (476 mg,39.0%).

[1267]¹H NMR (300 MHz, CDCl₃) δ2.40(m, 2H), 4.38(m, 4H), 6.97(m, 1H),7.62(d, 1H), 8.12(d, 1H), 12.88(m, 1H) ppm.

[1268] The nitro compound (0.48 g, 2.1 mmol) from Preparative Example 32Step A was dissolved in methanol (25 ml) and stirred with 10% Pd/C undera hydrogen gas atmosphere overnight. The reaction mixture was filteredthrough celite, the filtrate concentrated in vacuo to give the product(344 mg, 90%). ¹H NMR (300 MHz, CDCl₃) 82.52(m, 2H), 4.57(bs, 4H),6.75(m, 1H), 6.90(m, 2H), 12.71(bs, 1H) ppm.

Preparative Example 109

[1269]

[1270] In essentially the same manner as described in PreparativeExample 108 above, the morpholino-amine product was obtained.

Preparative Example 110

[1271]

[1272] Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane(100 mL). N,N′-Dimethylcarbamoyl chloride (1.0 mL, 0.011 mol) was addeddropwise to the solution at room temperature. The reaction was stirredfor one hour. After this time 1N potassium hydroxide (200 mL) was added.The layers were separated and the aqueous layer was extracted threetimes with dichloromethane. The organic fractions were combined anddried over sodium sulfate. Filtration and concentration provided theproduct, without further purification, as an oil (1.16 g, 13%).

[1273]¹H NMR (CDCl₃, 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H),3.20 (m, 4H).

[1274] MS: calculated: 157.12, found: 158.1.

Preparative Example 111

[1275]

[1276] Piperazine (4.9 g, 0.057 mol) was dissolved in 1N HCl (100 mL). Asolution of phenylsulfonylchloride (1.45 mL, 0.011 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (1.22 g, 9.4%).

[1277]¹H NMR (CDCl₃, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H).

[1278] MS: calculated: 226.08, found: 227.1.

Preparative Example 112

[1279]

[1280] Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane(100 mL). Methanesulfonyl chloride (0.85 mL, 0.011 mol) was addeddropwise to the solution at room temperature. The reaction was stirredfor 30 minutes. After this time 1N potassium hydroxide (200 mL) wasadded. The layers were separated and the aqueous layer was extractedthree times with dichloromethane. The organic fractions were combinedand dried over sodium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (1.07 g, 11%).

[1281]¹H NMR (CDCl₃, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H),3.20 (m, 4H).

[1282] MS: calculated: 164.06, found: 165.1.

Preparative Example 113

[1283]

[1284] Step A

[1285] Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved indichloromethane (100 mL). Propylisocyanate (1.51 mL, 0.0161 mol) wasadded to the solution at room temperature. The reaction was stirred forover night. After this time the reaction was diluted with 1N potassiumhydroxide (200 mL) and extracted six times with dichloromethane. Theorganic fractions were combined and dried over magnesium sulfate.Filtration and concentration provided the product as a solid.

[1286] Step B

[1287] The product of Step A above, was dissolved in a 30%trifluoroacetic acid/dichloromethane solution and stirred overnight.After this time a 1N potassium hydroxide solution (200 mL) was added tothe reaction. The aqueous layer was extracted a total of six times withdichloromethane. The organic fractions were combined and dried oversodium sulfate. Filtration and concentration provided the product (1.37g, 50%).

[1288]¹H NMR (CDCl₃, 300 MHz) 0.92 (t, 3H), 1.52 (m, 2H), 2.89 (m, 4H),3.01 (s, 1H), 3.18 (m, 2H), 3.37 (m, 4H), 4.61 (bs, 1H).

[1289] MS: calculated: 171.14, found: 172.0.

Preparative Example 114

[1290]

[1291] Piperazine (4.9 g, 0.0569 mol) was dissolved in 1N HCl (70 mL). Asolution of phenylchloroformate (1.43 mL, 0.0114 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (2.12 g, 18%).

[1292]¹H NMR (CDCl₃, 300 MHz) 1.78 (s, 1H), 2.91 (m, 4H), 3.59 (m, 4H),7.11 (2H), 7.19 (m, 1H), 7.36 (m, 2H).

[1293] MS: calculated: 206.24, found: 207.1.

Preparative Example 115-117

[1294] Following the procedure described for Example 112, the Productslisted in the table below were prepared using the commercially availablechloroformate shown and piperazine. 1. Yield (%) Example ChloroformateProduct 2. (M + 1)⁺ 115

1. 54% 2. 144.9 116

1. 17% 2. 173.0 117

1. 69% 2. 173.0

Preparative Example 118

[1295]

[1296] Step A

[1297] Boc-Piperazine (3.01 g, 0.0161 mol) was dissolved indichloromethane (100 mL) along with diisopropylethylamine (5.61 mL,0.0322 mol). Benzoylchloride (1.87 mL, 0.0161 mol) was added dropwise tothe solution at room temperature. The reaction was stirred for severalhours. After this time the reaction was concentrated and the product waspurified by column chromatography (10% MeOH/DCM). Boc-Protected productwas isolated as a solid (5.21 g).

[1298]¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H).

[1299] MS: calculated: 290.16, found: 290.8.

[1300] Step B

[1301] The product from Step A above, was dissolved in a 50%trifluoroacetic acid/dichloromethane solution and stirred overnight.After this time the reaction was diluted with 1N potassium hydroxide(200 mL) and the organic layer was separated. The aqueous phase was thenextracted six times with dichloromethane. The organic fractions werecombined and dried over magnesium sulfate. Filtration and concentrationprovided product (2.93 g).

[1302]¹H NMR (CDCl₃, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H),7.39 (s, 5H).

[1303] MS: calculated: 190.11, found: 191.1.

Preparative Example 119

[1304]

[1305] Step A

[1306] Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved indichloromethane (100 mL) along with diisopropylethylamine (3.1 mL,0.0177 mol). N,N′-dimethylsulfamoyl chloride (1.73 mL, 0.0161 mol) wasadded dropwise to the solution at room temperature. The reaction wasstirred for several hours. After this time the reaction was diluted withwater (100 mL). The layers were separated and the aqueous layer wasextracted six times with dichloromethane. The organic fractions werecombined and dried over magnesium sulfate. Filtration and concentrationprovided the product, without further purification, as a solid (4.53 g).

[1307]¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H),3.48 (m, 4H).

[1308] MS: calculated: 293.14, found: 194.1 (M-Boc)⁺.

[1309] Step B

[1310] The product from Step A above, was dissolved in a 30%trifluoroacetic acid/dichloromethane solution and stirred overnight.After this time the reaction was diluted with water and 1N potassiumhydroxide was used to make the aqueous layer slightly basic. The aqueouslayer was extracted a total of seven times with dichloromethane. Theorganic fractions were combined and dried over sodium sulfate.Filtration and concentration provided the product (2.96 g).

[1311]¹H NMR (CDCl₃, 300 MHz) 2.03 (s, 1H), 2.83 (s, 6H), 2.92 (m, 4H),3.23 (m, 4H).

[1312] MS: calculated: 193.09, found: 194.1.

Preparative Example 120

[1313]

[1314] In essentially the same manner as that described in PreparativeExample 105, Step 1, using 3-nitrobenzoic acid instead of3-nitrosalicylic acid, the methyl ester product was prepared.

[1315] The methyl ester (1.79 g, 6.1 mmol) from Step A above, wasdissolved in dioxane/water (20 mL/15 mL) at room temperature. Lithiumhydroxide (0.258 g, 6.2 mmol) was added to the solution. After a fewhours more lithium hydroxide was added (0.128 g, 3.0 mmol) and thereaction was stirred for another hour. After this time the reaction wasconcentrated and then taken up in water. The solution was extracted twotimes with ether. The aqueous phase was then acidified and extractedthree times with ethyl acetate. The organic fractions were then driedover sodium sulfate, filtered and concentrated. Product was isolated bycolumn chromatography (95% EtOAc/Hex, 0.05% HOAc) to give the product(1.66 g, 98%).

[1316]¹H NMR (300 MHz, CDCl₃) 1.49(m, 2H), 1.68(m, 1H), 1.82(m, 2H),2.44(m, 1H) 3.32(m, 1H), 3.58(m, 1H), 5.57(m, 1H), 7.65(m, 1H), 7.80(m,1H), 8.32(m, 2H), 10.04(bs, 1 Hppm).

[1317] The nitro compound was dissolved in an excess of methanol (20 mL)and covered by a blanket of argon. 5% Palladium on carbon was added(catalytic) and a hydrogen balloon was attached to the flask. Theatmosphere of the system was purged under vacuum and replaced withhydrogen. This step was repeated for a total of three times. Thereaction was then stirred under hydrogen overnight. After this time theballoon was removed and the solution was filtered through celitefollowed by several rinses with methanol. The filtrate was concentratedand dried on the vacuum line to provide the desired aniline product(1.33 g. 90%).

[1318]¹H NMR (300 MHz, CDCl₃) 1.40(m, 2H), 1.50(m, 1H), 1.68(m, 2H),2.33(m, 1H) 3.18(m, 1H), 3.62(m, 1H), 5.39(m, 1H), 6.12(bs, 2H), 6.75(m,2H), 7.12(m, 1H)ppm.

[1319] Mass Spectra, calculated: 248, found: 249.1 (M+1)⁺

Preparative Examples 121-123

[1320] Following the procedure described in Preparative Example 120, butusing the commercially available amine and benzoic acid indicated, theintermediate products in the table below were obtained. 1. Yield (%)Carboxylic 2. (M + 1)⁺ Ex. Acid Amine Product 3. Note 121

1. 21% 2. 251.0 122

1. 21% 2. 265.0 3. Skipped step B 123

1. 15% 2. 264.0 3. Skipped step B

Preparative Example 124

[1321]

[1322] Step A

[1323] 3-Nitrosalicylic acid (500 mg, 2.7 mmol),1,3-dicyclohexylcarbodiimide (DCC) (563 mg) and ethyl acetate (10 mL)were combined and stirred for 10 min. (R)-(−)-2-pyrrolidinemethanol(0.27 mL) was added and the resulting suspension was stirred at roomtemperature overnight. The solid was filtered off and the filtrate waseither concentrated down and directly purified or washed with 1N NaOH.The aqueous phase was acidified and extracted with EtOAc. The resultingorganic phase was dried over anhydrous MgSO₄, filtered and concentratedin vacuo. Purification of the residue by preparative platechromatography (silica gel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave thedesired compound (338 mg, 46%, MH⁺=267).

[1324] Step B

[1325] The product from Step A above was stirred with 10% Pd/C under ahydrogen gas atmosphere overnight. The reaction mixture was filteredthrough celite, the filtrate concentrated in vacuo, and the resultingresidue purified by column chromatography (silica gel, 4% MeOH/CH₂Cl₂saturated with NH₄OH) to give the product (129 mg, 43%, MH+=237).

Preparative Examples 125-145

[1326] Following the procedure described for Preparative Example 124,but using the commercially available amine or the amine from thePreparative Example indicated and 3-nitrosalicylic acid, the products inthe table below were obtained. Amine Comm. Avail./ 1. Yield (%) Ex. FromPrep. Ex. Product 2. (M + 1)⁺ 125

1. 37% 2. 298.1 126

1. 31% 2. 310.1 127

1. 68% 2. 294.1 128

1. 54% 2. 365.9 129

1. 45% 2. 316.1 130 110

1. 59% 2. 293.1 131 111

1. 32% 2. 362.0 132 114

1. 36% 2. 342.0 133 112

1. 65% 2. 300.0 134

1. 48% 2. 321.1 135

1. 50% 2. 300.1 136

1. 56% 2. 299.2 137 115

1. 79% 2. 280.1 138 116

1. 64% 2. 307.1 139

1. 73% 2. 304.2 140

1. 34% 2. 264.0 141 117

1. 40% 2. 307.1 142 113

1. 91% 2. 307.1 143 118

1. 9.0% 2. 326.0 144 119

1. 42% 2. 329.0 145

1. 6.5% 2. 236.1

Preparative Example 146

[1327]

[1328] Step A

[1329] To a solution of tosylaziridine [J. Am. Chem. Soc. 1998, 120,6844-6845) (0.5 g, 2.1 mmol) and Cu(acac)₂ (55 mg, 0.21 mmol) in THF (5mL) at 0° C. was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8mL) dropwise over 20 min. The resulting solution was allowed togradually warm to rt and was stirred for 12 h. Sat. aq. NH₄Cl (5 mL),was added and the mixture was extracted with Et₂O (3×15 mL). The organiclayers were combined, washed with brine (1×10 mL), dried (MgSO₄) andconcentrated under reduced pressure. The crude residue was purified bypreparative TLC eluting with hexane/EtOAc (4:1) to afford 0.57 g (86%yield) of a solid. The purified tosylamine was taken on directly to thenext step.

[1330] Step B

[1331] To a solution of tosylamine (0.55 g, 1.75 mmol) in NH₃ (20 mL) at−78° C. was added sodium (0.40 g, 17.4 mmol). The resulting solution wasstirred at −78° C. for 2 h whereupon the mixture was treated with solidNH₄Cl and allowed to warm to rt. Once the NH₃ had boiled off, themixture was partitioned between water (10 mL) and CH₂Cl₂ (10 mL). Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×10 mL). The organic layers were combined,), dried (NaSO₄), andconcentrated under reduced pressure to a volume of ˜20 mL. 4N HCl indioxane (5 mL) was added and the mixture was stirred for 5 min. Themixture was concentrated under reduced pressure and the resultant cruderesidue was recrystallized from EtOH/Et₂O to afford 0.30 g (87% yield)of a solid.

Preparative Examples 147-156.10

[1332] Following the procedure set forth in Preparative Example 146 butusing the requisite tosylaziridines and Grignard reagents listed in theTable below, the following racemic hydrochloride products were obtained.Prep Tosyl Grignard Amine Ex. aziridine Reagent hydrochloride 1. Yield(%) 147

MeMgBr

1. 19% 148

EtMgBr

1. 56% 149

n-PrMgBr

1. 70% 150

i-PrMgCl

1. 41% 151

BnMgCl

1. 61% 152

MeMgBr

1. 61% 153

EtMgBr

1. 66% 154

n-PrMgBr

1. 80% 155

i-PrMgBr

1. 27% 156

BnMgCl

1. 79% 156.1

52% 156.2

49% 156.3

61% 156.4

57% 156.5

64% 156.6

64% 156.7

45% 156.8

23% 156.9

40% 156.10

15%

Preparative Example 156.11

[1333]

[1334] Step A

[1335] To a solution of the amine (118 mg) from Preparative Example 148in CH₂Cl₂ (10 ml) was added triethylamine (120 ul), R-Mandelic Acid (164mg), DCC (213 mg) and DMAP (8.8 mg)and let stir for 40 hr. The mixturewas diluted with CH₂Cl₂ and washed with saturated ammonium chloride,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by preparative plate chromatography (Hex/EtOAc4:1) to afford both isomers (A, 86 mg, 45%) (B, 90 mg, 48%).

[1336] Step B

[1337] To isomer B (90 mg) from above in dioxane (5 ml) was added 6MH₂SO₄ (5 ml). The reaction was heated to 80° C. over the weekend. 2MNaOH added to basify the reaction and extracted with ether. Ether layerwashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was stirred in 4N HCl in dioxane for 30 min,concentrated in vacuo and recrystallized in EtOH/ether to afford 55 mgof product (98%).

[1338] Step C

[1339] Isomer A (86 mg) was reacted following the procedure set forth inStep B above to give the amine salt.

Preparative Example 156.12

[1340]

[1341] The above nitro compound was reduced following the PreparativeExample 2, Step B.

Preparative Example 156.13

[1342]

[1343] To a solution of 1,2-phenylenediame (1.5 g) in CH₂Cl₂ (30 ml) at0° C. was added TEA (2.91 ml), followed by dropwise addition of MeSO₂Cl(1.07 ml). The mixture was allowed to warm to room temperature and stirovernight. 1M HCl added and the layers were separated. The aqueous layerwas adjusted to pH=11 with solid NaOH, extracted with CH₂Cl₂. Thebasified aqueous layer was then neutralized using 3N HCl and extractedwith CH₂Cl₂, dried with Na₂SO₄, filtered, and concentrated in vacuo togive 1.8 g of product (71%).

Preparative Example 156.14

[1344]

[1345] The above compound was prepared using the procedure set forth inPreparative Example 156.13, but using PhSO₂Cl.

Preparative Example 156.15

[1346]

[1347] The nitro compound was reduced following a similar procedure asin Preparative Example 2, Step B.

Preparative Example 156.16

[1348]

[1349] Step A

[1350] The known acid (410 mg) above (J. Med. Chem. 1996, 34,4654.) wasreacted following the procedure set forth in Preparative Example 2, StepA to yield 380 mg of an oil (80%).

[1351] Step B

[1352] The amide (200 mg) from above was reacted following the procedureset forth in Preparative Example 2, Step B to yield 170 mg of an oil(100%).

Preparative Example 156.17

[1353]

[1354] Step A

[1355] To a solution of ketone (500 mg) in EtOH/water (3:1, 4 ml) atroom temperature was added hydroxylamine hydrochloride (214 mg) followedby NaOH to afford a heterogenous mixture. The reaction was not completeso another equivalent of hydroxylamine hydrochloride was added andrefluxed overnight. The reaction was cooled to 0° C. and treated with 3NHCl and extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to give 500 mg of product (92%).

[1356] Step B

[1357] To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was addedLiAIH₄ (266 mg) portionwise. The heterogenous solution was stirred atroom temperature for 14 hr and then refluxed for 8 hr. The solution wascooled to 0° C. and water, 2M NaOH, water and ether were added to thereaction. The mixture was filtered through a celite pad. The filtratewas treated with 3N HCl. The aqueous layer was cooled to 0° C., basifiedwith NaOH pellets and extracted with ether. The ether layer was driedover MgSO₄, filtered, and concentrated in vacuo to afford the product(143 mg, 69%).

Preparative Example 156.18

[1358]

[1359] Step A

[1360] Methoxyacetic acid (14 mL) in CH₂Cl₂ (120 mL) and cooled in anice-water bath was treated with DMF (0.9 mL) and oxalyl chloride (21mL). After stirring at RT overnight, the mixture was concentrated invacuo and redissolved in CH₂Cl₂ (120 mL). N-methyl-N-methoxylamine (20g) was added and the mixture stirred at RT overnight. Filtration andconcentration in vacuo afforded the desired amide (21 g, 89%).

[1361] Step B

[1362] To a solution of the above amide (260 mg) in THF (5 ml) at −78°C. was added a solution of 2-thienyllithium (1M in THF, 2.15 ml). Thesolution was stirred for 2 hr at −78° C. and warmed to −20° C. for anadditional 2 hr. The reaction was quenched with saturated ammoniumchloride and extracted with CH₂Cl₂, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to give 250 mg of product(82%).

[1363] Step C

[1364] The ketone from above (250 mg) was reacted via the procedure setforth in Preparative Example 156.17 Steps A and B to yield 176 mg of theamine (79%).

Preparative Example 156.19

[1365]

[1366] Step A

[1367] To a solution of 3-chlorothiophene (1.16 ml) in ether (20 ml) at−10° C. was added n-BuLi (2.5M in hexane, 5 ml). After solution wasstirred at −10° C. for 20 min, propionaldehyde (0.82 ml) in ether (20ml) was added dropwise and let warm to room temperature slowly. Thereaction was quenched with saturated ammonium chloride and extractedwith CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give 1.37 g of product (62%).

[1368] Step B

[1369] The alcohol from Step A above was reacted via the procedures setforth in Preparative Example 75.75, Steps B and C to give the amine.

Preparative Example 156.20

[1370]

[1371] Step A

[1372] To a solution of magnesium metal (360 mg) in THF (15 ml) at 0° C.was added 2-bromothiophene (1.45 ml) in THF (10 ml) dropwise over 20min. The solution was warmed to room temperature for 3 hr, recooled to0° C. whereupon a solution of cyclopropylacetonitrile (1 g) in ether (30ml) was added dropwise via a syringe and let warm to room temperatureand stir overnight. 3M HCl was added and washed with CH₂Cl₂. The aqueouslayer was basified with NaOH pellets and extracted with ether, driedwith Na₂SO₄, filtered, and concentrated in vacuo to give 625 mg ofproduct (68%).

[1373] Step B

[1374] The ketone was reacted via the procedure set forth in PreparativeExample 156.17 Step A to give the oxime.

[1375] Step C

[1376] The oxime from above was reacted via the procedure set forth inPreparative Example 156.17 Step B to give the amine.

Preparative Example 156.21

[1377]

[1378] Step A

[1379] To a solution of CH₃ONHCH₃.HCl (780 mg) and acid chloride (1 g)in CH₂Cl₂ at 0° C. was added dry pyridine (1.35 ml) to afford aheterogenous mixture The solution was warmed to room temperature andstirred overnight. 1 M HCl was added to the reaction and the organiclayer was separated, washed with brine, dried with Na₂SO₄, filtered, andconcentrated in vacuo to give 1 g of product (85%).

[1380] Step B

[1381] To a solution of Etl (614 ul) in ether (5 ml) at −78° C. wasadded t-BuLi (1.7M in pentane, 9 ml) dropwise. The mixture was warmed toroom temperature for 1 hr, cooled to −78° C. where the amide (1 g) fromStep A in THF (4 ml) was added and allowed to warm to 0° C. for 2 hr. 1MHCl was added to the reaction and extracted with CH₂Cl₂, washed withbrine, dried with Na₂SO₄, filtered, and concentrated in vacuo to give500 mg of product (63%).

[1382] Step C

[1383] To a solution of ketone (800 mg) in THF/water (10:1, 20 ml) at 0°C. was added sodium borohydride (363 mg) portionwise. The solution wasstirred for 2 hr at 0° C. The mixture was concentrated in vacuo, theresidue was dissolved in CH₂Cl₂, washed with 1N NaOH and brine, driedwith Na₂SO₄, filtered, and concentrated in vacuo to give 560 mg ofproduct (69%).

[1384] Step D

[1385] The alcohol from above was reacted via the procedures set forthin Preparative Example 75.75, Steps B and C to give the amine (176 mg,59%).

Preparative Example 156.22

[1386]

[1387] Step A

[1388] Cyclopropylacetonitrile (12 mmol) in Et₂O (50 mL) at 0° C. wastreated with PhMgBr (14 mmol) and the mixture was stirred for 2 hrs at0° C., then at RT overnight. Hydrochloric acid (3M) was added, and afterstirring for an additional 12 hrs, the mixture was extracted withCH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered and concentratedin vacuo to give the desired ketone (1.34 g, 70%).

[1389] Step B

[1390] Following the procedures set forth in Preparative Example 156.20Steps B and C, the amine was prepared.

Preparative Example 156.23

[1391]

[1392] The above amine was prepared using the procedures set forth in WOPatent Publication 98/11064.

Preparative Example 157

[1393]

[1394] Step A

[1395] By taking the known carboxylic acid [J. Med. Chem. 1996, 39,4654-4666] and subjecting it to the conditions outlined in PreparativeExample 112, the product can be prepared.

[1396] Step B

[1397] Following a similar procedure used in Preparative Example 2, StepA, except using dimethylamine and the compound from Step A above, theproduct can be prepared.

[1398] Step C

[1399] Following a similar procedure used in Preparative Example 2, StepB, except using the compound from Step B above, the product can beprepared.

Preparative Example 158

[1400]

[1401] Following a similar procedure used in Preparative Example 157,Steps A-C, except using trifluoromethylsulfonylchloride in Step A above,the product can be prepared.

Preparative Example 500.1

[1402]

[1403] Step A

[1404] By using the nitro-amide from Preparative Example 13.3, Step A,the amidine structure can be prepared following a similar procedure tothat in Tetrahedron Lett., 2000, 41 (11), 1677-1680.

[1405] Step B

[1406] By using the product from Step A and the procedure set forth inPreparative Example 2, Step B, one could obtain the desiredamine-amidine.

Alternate Preparative Example 500.2

[1407]

[1408] Step A

[1409] By treating the nitro-amide from Preparative Example 13.3, Step Bwith POCl₃ and subsequently MeNH₂, according to procedures known in theart, one would obtain the desired compound.

[1410] Step B

[1411] By treating the product from Step A according to the procedureset forth in Preparative Example 13.3, Step E, one could obtain thedesired compound.

[1412] Step C

[1413] By using the product from Step B and the procedure set forth inPreparative Example 2 Step B, one would obtain the desired compound.

Preparative Example 500.3

[1414]

[1415] Step A

[1416] By following a similar procedure as that described in Zh. Obshch.Khim., 27, 1957, 754, 757., but instead using 2,4-dichlorophenol anddimethylphosphinic chloride, one would obtain the desired compound.

[1417] Step B

[1418] By following a similar procedure as that described in J.Organomet. Chem.; 317, 1986, 11-22, one would obtain the desiredcompound.

[1419] Step C

[1420] By following a similar procedure as that described in J. Amer.Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1421] Step D

[1422] By following a similar procedure as that described in J. Med.Chem., 27, 1984, 654-659, one would obtain the desired compound.

Alternate Preparative Example 500.4

[1423]

[1424] Step A

[1425] By following a similar procedure as that described inPhosphorous, Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129, butinstead using 4-chlorophenol, one would obtain the desired compound.

[1426] Step B

[1427] By using a similar procedure as that in Phosphorous, SulfurSilicon Relat. Elem.; EN; 61, 12, 1991, 119-129, but instead usingMeMgBr, the desired compound could be prepared.

[1428] Step C

[1429] By following a similar procedure as that described in J. Amer.Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1430] Step D

[1431] By following a similar procedure as that described in J. Med.Chem., 27, 1984, 654-659, one would obtain the desired compound.

Preparative Example 500.5

[1432]

[1433] By following a similar procedure as that set forth in J. Org.Chem. 1998, 63, 2824-2828, but using CH₃CCMgBr, one could obtain thedesired compound.

Preparative Example 500.6

[1434]

[1435] Step A

[1436] By following the procedure set forth in Preparative Example 13.1,Step B using 3-methoxythiophene, one can obtain the desired product.

[1437] Step B

[1438] By using the product from step A and following the procedure setforth in Preparative Example 13.19, Step E, the desired compound can beobtained.

[1439] Step C

[1440] By using the product from Step B and following the procedure setforth in Preparative Example 13.29, Step D, one can obtain the desiredcompound.

[1441] Step D

[1442] By using the product from Step C and following the procedure setforth in Preparative Example 13.3, Step B, the desired compound can beobtained.

[1443] Step E

[1444] By treating the product from Step D with n-BuLi at −78° C. in THFand quenching the resulting anion with CO₂ according to standardliterature procedure, one would obtain the desired compound followingaqueous acid work up.

[1445] Step F

[1446] By using the product from Step E and the procedure set forth inPrepartive Example 13.19, Step C, one could obtain the desired compound.

[1447] Step G

[1448] By using the product from step F and following the procedure setforth in Preparative Example 13.19, Step E, the desired compound can beobtained.

[1449] Step H

[1450] By using the product from Step G and following the procedure setforth in Preparative Example 2, Step B, the desired compound can beobtained.

[1451] Step I

[1452] By using the product from Step H and following the procedure setforth in Preparative Example 19, the desired compound can be prepared.

Example 200

[1453]

[1454] To a solution of the HCl salt product (83 mg, 0.50 mmol) fromPreparative Example 24, in EtOH (3 mL) at room temperature was addedEt₃N (55 μL, 0.50 mmol) and the mixture was stirred for 10 min. Thecyclobutenedione (100 mg, 0.33 mmol) from Preparative Example 19 in EtOHwas then added in a single portion and the mixture was stirred for 12 hat room temperature. The mixture was concentrated under reduced pressureand was purified by preparative TLC (4×1000 μM plates) eluting withCH₂Cl₂/MeOH (25:1) to afford 116 mg (91% yield) of the desired productas a solid [MH+389.1, mp 241-243° C].

Examples 201-209

[1455] Following the procedure set forth in Preparative Example 200 butusing the appropriate amine hydrochlorides from Preparative Examples25-33 as identified and the cyclobutenedione intermediate fromPreparative Example 19, the cyclobutenedione products in the Table belowwere obtained. 1. Yield (%) (Prep Ex.) 2. MH⁺ Ex. Amine Product 3. mp (°C.) 201 (25)

1. 89% 2. 375.1 3. 255.5-257.3 202 (26)

1. 92% 2. 465.1 3. 149.0-152.3 203 (27)

1. 68% 2. 451.1 3. 282-284 204 (28)

1. 74% 2. 493.1 3. 141 205 (29)

1. 48% 2. 479.1 3. 142 206 (30)

1. 41% 2. 479.1 3. 142 207 (31)

1. 59% 2. 479.1 3. 141 208 (32)

1. 34% 2. 493.1 3. 140 209 (33)

1. 40% 2. 493.1 3. 142 209.1 (33.1)

1. 59% 2. 143-145

Example 209.2

[1456]

[1457] The crude amine product from Preparative Example 33.2 and thecyclobutendione component from Preparative Example 19.1(36 mg) weredissolved in MeOH/DIEA (2.5 ml/5/1) and irradiated via microwave (50W, 1hr). The reaction was concentrated in vacuo and purified by Gilsonsemi-prep. HPLC to give the final product (68%, MH+=485.2).

Examples 209.3-209.50

[1458] Following the procedure set forth in Example 209.2, but using theprepared amine from the Preparative Example indicated in the Tablebelow, the following cyclobutenedione products were obtained. (PrepEx.) 1. Yield (%) Ex. Amine Product 2. MH⁺ 209.3 (33.3)

1. 50% 2. 541.2 209.4 (33.4)

1. 32% 2. 549.1 209.5 (33.5)

1. 65% 2. 493.1 209.6 (33.6)

1. 64% 2. 491.1 209.10 (33.7)

1. 90% 2. 457.2 209.11 (33.8)

1. 35% 2. 505.0 209.12 (33.9)

1. 70% 2. 493.1 209.13 (33.10)

1. 75% 2. 480.2 209.14 (33.11)

1. 74% 2. 465.1 209.15 (33.12)

1. 62% 2. 479.1 209.16 (33.13)

1. 31% 2. 466.2 209.17 (33.14)

1. 79% 2. 495.2 209.18 (33.15)

1. 99% 2. 479.2 209.19 (33.16)

1. 47% 2. 466.2 209.20 (33.17)

1. 72% 2. 479.1 209.21 (33.18)

1. 92% 2. 493.1 209.22 (33.19)

1. 47% 2. 499.1 209.23 (33.20)

1. 7% 2. 490.0 209.24 (33.21)

1. 15% 2. 533.1 209.25 (33.22)

1. 88% 2. 451.1 209.26 (33.23)

1. 26% 2. 523.0 209.27 (33.24)

1. 54% 2. 433.1 209.28 (33.25)

1. 59% 2. 466.2 209.29 (33.26)

1. 66% 2. 560.2 209.30 (33.27)

1. 98% 2. 495.1 209.31 (33.28)

1. 99% 2. 471.2 209.32 (33.29)

1. 99% 2. 471.2 209.33 (33.30)

1. 18% 2. 524.2 209.34 (33.31)

1. 78% 2. 479.2 209.35 (33.32)

1. 71% 2. 459.2 209.36 (33.33)

1. 5% 2. 491.0 209.37 (33.34)

1. 27% 2. 501.1 209.38 (33.35)

1. 26% 2. 533.1 209.39 (33.36)

1. 48% 2. 451.1 209.40 (33.37)

1. 99% 2. 455.1 209.41 (33.38)

1. 88% 2. 527.1 209.42 (33.39)

1. 74% 2. 485.2 209.43 (33.40)

1. 20% 2. 492.5 209.44 (33.41)

1. 68% 2. 541.1 209.45 (33.42)

1. 13% 2. 508.9 209.46 (33.43)

1. 86% 2. 479.1 209.47 (33.44)

1. 34% 2. 507.0 209.48 (33.45)

1. 56% 2. 429.1 209.49 (33.46)

1. 18% 2. 495.0 209.50 (33.47)

1. 22% 2. 501.0

Example 210

[1459]

[1460] To a solution of amine (0.17 g, 1 mmol) from Preparative Example34 in EtOH (3 mL) at room temperature was added the cyclobutenedionefrom Preparative Example 19 (100 mg, 0.33 mmol) in one portion. Theresulting mixture was stirred for 5 h (until TLC analysis revealedreaction complete) and was concentrated under reduced pressure. Thecrude residue was redissolved in CH₂Cl₂ (15 mL) and was washedsequentially with 10% KH₂PO₄ (2×15 mL) and brine (1×15 mL). The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure toafford the crude adduct. The crude product was purified by prep TLC(4×1000 uM plates) eluting with CH₂Cl₂/MeOH (20:1) to afford 83 mg (59%yield) of the desired product as a solid.

Examples 211-260

[1461] Following the procedure set forth in Example 210 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the Table below, the following cyclobutenedioneproducts were obtained. 1. Yield (%) (Prep Ex) 2. MH⁺ Ex. Amine Product3. mp (° C.) 211

1. 75% 2. 412.1 3. 126 212

1. 42% 2. 438.1 3. 106 213

1. 73% 2. 428.1 3. 139 214

1. 40% 2. 462.1 3. 160 215

1. 52% 2. 408.1 3. 126 216

1. 32% 2. 478.1 3. 176 217

1. 50% 2. 412.1 3. 126 218

1. 55% 2. 478.1 3. 100 219

1. 67% 2. 438.1 3. 122 220

1. 73% 2. 462.1 3. 118 221

1. 67% 2. 424.1 3. 100 222

1. 61% 2. 478.1 3. 114 223

1. 50% 2. 408.1 3. 157-159 224

1. 75% 2. 366.1 3. 110-112 225

1. 81% 2. 380.1 3. 118-120 226

1. 69% 2. 394.1 3. 123-125 227

1. 80% 2. 367.1 3. 122-125 228

1. 72% 2. 381.1 3. 133-135 229

1. 81% 2. 395.1 3. 141-145 230

1. 75% 2. 356.1 3. 103-104 231

1. 24% 2. 370.1 3. 101 232

1. 16% 2. 384.1 3. 70 233

1. 72% 2. 373.4 3. 104-106 234

1. 34% 2. 387.1 3. 99 235

1. 48% 2. 380.1 3. 118-120 236

1. 72% 2. 380.1 3. 119-120 237

1. 72% 2. 398.1 3. 121-123 238

1. 44% 2. 398.1 3. 121-123 239

1. 60% 2. 394.1 3. 123-124 240

1. 52% 2. 394.1 3. 122-124 241

1. 34% 2. 428.4 3. 157-159 242

1. 70% 2. 412.1 3. 109-112 243

1. 69% 2. 412.1 3. 110-112 244

1. 89% 2. 412.1 3. 126 245

1. 81% 2. 412.1 3. 126 246

1. 65% 2. 424.1 3. 121-124 247

1. 73% 2. 424.1 3. 122-124 248

1. 29% 2. 372.1 3. 219-221 249

1. 66% 2. 394.1 3. 132-135 250

1. 72% 2. 332 251

1. 74% 2. 408.1 3. 121-123 252

1. 76% 2. 408.1 3. 102-104 253

1. 72% 2. 438.1 3. 75-77 254

1. 80% 2. 392.1 3. 98-101 255

1. 72% 2. 420.1 3. 200-205 256

1. 75% 2. 434.1 3. 138-140 257

1. 67% 2. 410.1 3. 116-118 258

1. 76% 2. 424.1 3. 108-110 259

1. 72% 2. 430.1 3. 125 260

1. 78% 2. 422.1 3. 127 260.1

1. 74% 2. 426.1 3. 114 DEC 260.2

1. 85% 2. 436.1 3. 143 DEC 260.3

1. 56% 2. 474.1 3. 121-123 260.4

1. 71% 2. 500.1 3. 97 (DEC) 260.6

1. 61% 2. 465 3. 102-107 260.7

1. 78% 2. 422.1 3. 114 DEC 260.8

1. 35% 2. 486.1 3. 103-105 260.9

1. 79% 2. 470 3. 110-115 260.10

1. 62% 2. 462.1 3. 110 DEC 260.11

1. 61% 2. 446.1 3. 118 DEC 260.12

1. 58% 2. 480.1 3. 111 DEC 260.13

1. 87% 2. 438.1 3. 122 260.14

1. 74% 2. 408.1 3. 128-130 260.15

1. 78% 2. 430.1 3. 117 DEC 260.16

1. 81% 2. 452.1 3. 139 260.17

1. 85% 2. 426.1 3. 126 260.18

1. 50% 2. 482.1 3. 114-116 260.19

1. 64% 2. 450.1 3. 129 260.20

1. 72% 2. 424.1 3. 116 260.21

1. 35% 2. 434.1 3. 124 260.22

1. 58% 2. 420.1 3. 107-109 260.23

1. 69% 2. 440.1 3. 169 260.24

1. 15% 2. 404.1 3. 103-105 260.25

1. 92% 2. 434.1 3. 129 260.26

1. 77% 2. 434.1 3. 133 260.27

1. 73% 2. 434.1 3. 138 260.28

1. 37% 2. 434.1 3. 133

Example 261

[1462]

[1463] To a solution of the amine (77 μL, 0.66 mmol) in EtOH (3 mL) atroom temperature was added the product from Preparative Example 19 (100mg, 0.33 mmol) in one portion. The resulting mixture was stirred for 5 h(until TLC analysis revealed reaction complete) and was thenconcentrated under reduced pressure. The crude residue was redissolvedin CH₂Cl₂ (15 mL) and was washed sequentially with 10% KH₂PO₄ (2×15 mL)and brine (1×15 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure to afford the crude adduct. Thecrude product was purified by prep TLC (4×1000 uM plates) eluting withCH₂Cl₂/MeOH (20:1) to afford 82 mg (72% yield) of the desired product asa solid. (mp 126.0-128.0° C., MH⁺ 346)

Examples 262-360.117

[1464] Following the procedure set forth in Example 261 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the table below, the following cyclobutenedioneproducts were obtained. 1. Yield (%) 2. MH⁺ Ex. Amine Product 3. mp (°C.) 262

1. 74% 2. 330.1 3. 112-115 263

1. 64% 2. 344.1 3. 120-122 264

1. 72% 2. 358.4 3. 129-132 265

1.76% 2. 372.1 3. 141-143 266

1. 57% 2. 372.1 3. 102 267

1. 65% 2. 386.1 3. 146 268

1. 65% 2. 464.1 3. 110-112 269

1. 85% 2. 464.1 3. 111-113 270

1. 49% 2. 374.1 3. 146 271

1. 69% 2. 374.1 3. 158-162 272

1. 54% 2. 430.1 3. 108 273

1. 65% 2. 430.1 3. 110 274

1. 53% 2. 388.1 3. 136 275

1. 30% 2. 388.1 3. 114 276

1. 53% 2. 402.1 3. 126 277

1. 68% 2. 402.1 3. 116 278

1. 64% 2. 372.1 3. 106 279

1. 69% 2. 434.1 3. 141-143 280

1. 51% 2. 434.1 3. 148-150 281

1. 71% 2. 406.1 3. 146-148 282

1. 66% 2. 406.1 3. 141-144 283

1. 70% 2. 450.1 3. 97-99 284

1. 25% 2. 360.1 3. 139 285

1. 78% 2. 416.1 3. 94 286

1. 49% 2. 372.1 3. 139 287

1. 95% 2. 386.1 3. 139 288

1. 32% 2. 348 3. 130-133 289

1. 72% 2. 410.1 3. 138 290

1. 72% 2. 410.1 3. 132-134 291

1. 75% 2. 318.1 3. 96-98 292

1. 72% 2. 430.1 3. 125 293

1. 51% 2. 348 3. 109-111 294

1. 84% 2. 374 3. 150.3 295

1. 56% 2. 386 3. 142.3 296

1. 38% 2. 382 3. 173.4 297

1. 13% 2. 370 3. 135.1 298

1. 47% 2. 424 3. 231.2-234.5 299

1. 34% 2. 316 3. 209.5 300

1. 92% 2. 392 3. 152.7 301

1. 52% 2. 346 3. 124.7 302

1. 51% 2. 346 3. 139.2 303

1. 29% 2. 408 3. 105 304

1. 24% 2. 372 3. 223.2 305

1. 25% 2. 442 3. 219.0 306

1. 83% 2. 386 3. 145 307

1. 58% 2. 400 3. 99.6 308

1. 60% 2. 414 3. 123.6 309

1. 44% 2. 412 3. 146.7 310

1. 39% 2. 432 3. 156.6 311

1. 65% 2. 448 3. 162.8 312

1. 53% 2. 449 3. 139.7 313

1. 64% 2. 454 3. 143.2 314

1. 35% 2. 428 3. 146.8 315

1. 72% 2. 476 3. 139.4 316

1. 36% 2. 402 3. 89.6 317

1. 62% 2. 400 3. 130.2 318

1. 46% 2. 400 3. 123.6 319

1. 64% 2. 400 3. 132.5 320

1. 79% 2. 406 3. 123.3 321

1. 17% 2. 440 3. 157.6 322

1. 58% 2. 428 3. 167.9 323

1. 50% 2. 422 3. 150.2 324

1. 20% 2. 462 3. 113.9 325

1. 95% 2. 360 3. 129.2 326

1. 97% 2. 360 3. 131.5 327

1. 39% 2. 318 3. 138.5 328

1. 54% 2. 408 3. 152.3 329

1. 62% 2. 346 3. 134.8 330

1. 55% 2. 346 3. 145.1 331

1. 61% 2. 400 3. 137.6 332

1. 42% 2. 374 3. 155.1 333

1. 45% 2. 348 3. 108-110 334

1. 29% 2. 424 3. 116 335

1. 15% 2. 414 3. 108-110 336

1. 75% 2. 408 3. 116 337

1. 75% 2. 408 3. 116 338

1. 59% 2. 424 3. 115-117 339

1. 72% 2. 424 3. 157-159 340

1. 19% 2. 332 3. 131 341

1. 86% 2. 360 3. 127 342

1. 98% 2. 346 3. 128 343

1. 80% 2. 374 3. 131.5 344

1. 46% 2. 374 3. 102 345

1. 75% 2. 388 3. 104 346

1. 76% 2. 438 3. 95 347

1. 72% 2. 424 3. 163-165 348

1. 73% 2. 438 3. 96-98 349

1. 53% 2. 362 3. 89-91 350

1. 59% 2. 362 3. 90-92 351

1. 61% 2. 362 3. 120-122 352

1. 70% 2. 362 3. 121-123 353

1. 23% 2. 371 3. 126 354

1. 79% 2. 370 3. 108 355

1. 80% 2. 370 3. 106 356

1. 56% 2. 450 3. 138-140 357

1. 76% 2. 398 3. 116 358

1. 85% 2. 384 3. 100 359

1. 59% 2. 332 3. 138.6 360

1. 47% 2. 332 3. 141.6 360.1

1. 89% 2. 356.1 3. 133-135 360.2

1. 65% 2. 334.1 3. 121-122 360.3

1. 60% 2. 348.1 3. 94-96 360.4

1. 29% 2. 414.1 3. 108-110 3605.

1. 67% 2. 348.1 3. 95-96 360.6

1. 62% 2. 414.1 3. 113-115 360.7

1. 68% 2. 414.1 3. 114-116 360.8

1. 74% 2. 374 3. 129.8 360.9

1. 61% 2. 388 3. 123.1 360.10

1. 53% 2. 388 3. 117.2 360.11

1. 37% 2. 388 3. 129.9 360.12

1. 62% 2. 374 3. 126.1 360.13

1. 71% 2. 400.1 3. 106-109 360.14

1. 66% 2. 400.1 3. 106-109 360.15

1. 69% 2. 372 3. 138.7 360.16

1. 54% 2. 346 3. 123.6 360.17

1. 53% 2. 388 3. 116.9 360.18

1. 87% 2. 384.1 3. 136 360.19

1. 92% 2. 384.1 3. 136 360.20

1. 27% 2. 386.1 3. 109-112 360.12

1. 31% 2. 400.1 3. 117-120 360.22

1. 61% 2. 396.1 3. 129 360.23

1. 69% 2. 396.1 3. 126 360.24

1. 74% 2. 398.1 3. 123 360.25

1. 76% 2. 398.1 3. 123 360.26

1. 60% 2. 384.1 3. 103-105 360.27

1. 67% 2. 384.1 3. 104‥106 360.28

1. 70% 2. 386.1 3. 103-105 360.29

1. 64% 2. 400.1 3. 109-111 360.30

1. 63% 2. 398.1 3. 99-101 360.31

1. 57% 2. 398.1 3. 99-101 360.32

1. 45% 2. 400 3. 104.6 360.33

1. 44% 2. 386 3. 143 360.34

1. 73% 2. 356.1 3. 218-220 360.35

1. 97% 2. 406.1 3. 154 360.36

1. 77% 2. 414.1 3. 122-124 360.37

1. 70% 2. 412.1 3. 99-101 360.38

1. 69% 2. 416.1 3. 107-109 360.39

1. 43% 2. 454.1 3. 128-130 360.40

1. 40% 2. 374.1 3. 132-136 360.41

1. 60% 2. 345.1 3. 205-207 360.42

1. 96% 2. 412.1 3. 112 360.43

1. 30% 2. 434.1 3. 117-119 360.44

1. 96% 2. 410.1 3. 139 360.45

1. 65% 2. 384.1 3. 87-89 360.46

1. 50% 2. 434.1 3. 123-125 360.47

1. 74% 2. 412.1 3. 84-86 360.48

1. 73% 2. 400.1 3. 136-140 360.49

1. 74% 2. 412.1 3. 103-105 360.50

1. 63% 2. 434.1 3. 114-117 360.51

1. 74% 2. 414.1 3. 130-133 360.52

1. 71% 2. 426.1 3. 138 360.53

1. 41% 2. 414 3. 139-141 360.54

1. 32% 2. 426 3. 148-150 360.55

1. 57% 2. 428 3. 159-163 360.56

1. 44% 2. 464.1 3. 86-88 360.57

1. 37% 2. 442 3. 158-162 360.58

1. 53% 2. 494.1 3. 148-151 360.59

1. 63% 2. 528.1 3. 90-95 360.60

1. 73% 2. 438.1 3. 116 360.61

1. 55% 2. 494.1 3. 133-135 360.62

1. 83% 2. 412.1 3. 119 360.63

1. 66% 2. 440.1 3. 110 360.64

1. 49% 2. 410.1 3. 97 360.65

1. 40% 2. 442.1 3. 157-160 360.66

1. 75% 2. 400 3. 136-140 360.67

1. 63% 2. 528.1 3. 106-108 360.68

1. 10% 2. 401.1 3. 111-113 360.69

1. 5% 2. 426.1 360.70

1. 56% 2. 442.1 3. 152-154 360.71

1. 46% 2. 414.1 3. 122-124 360.72

1. 62% 2. 385.1 3. 130-133 360.73

1. 41% 2. 399.1 3. 83-85 360.74

1. 70% 2. 414.1 3. 98-101 360.75

1. 62% 2. 441.1 3. 98-102 360.76

1. 79% 2. 464.1 3. 111 360.77

1. 79% 2. 418.1 3. 107 360.78

1. 65% 2. 400.1 3. 109-112 360.79

1. 21% 2. 428.1 3. 126 360.80

1. 55% 2. 493.1 3. 155-158 360.81

1. 67% 2. 428.1 3. 138-140 360.82

1. 68% 2. 426.1 3. 121-123 360.83

1. 25% 2. 427.1 3. 139 360.84

1. 62% 2. 413.1 3. 128 360.85

1. 49% 2. 460.1 3. 112-114 360.86

1. 71% 2. 434.1 3. 91-93 360.87

1. 57% 2. 411.1 3. 125 360.88

1. 12% 2. 400.1 3. 131-133 360.89

1. 60% 2. 464.1 3. 111-113 360.90

1. 60% 2. 418.1 3. 113 360.91

1. 55% 2. 415.1 3. 140-143 360.92

1. 55% 2. 429 3. 185-190 360.93

1. 3% 2. 447.1 360.94

1. 71% 2. 452.1 3. 106 360.95

1. 44% 2. 439.1 3. 112 360.96

1. 71% 2. 464.1 3. 111-113 360.97

1. 70% 2. 398.1 3. 106-108 360.98

1. 46% 2. 426.1 3. 140-142 360.99

1. 62% 2. 399.1 3. 109-112 360.100

1. 60% 2. 466.1 3. 129-131 360.101

1. 49% 2. 446.1 3. 146 360.102

1. 48% 2. 432.1 3. 116 360.103

1. 62% 2. 418.1 3. 126 360.104

1. 47% 2. 430.1 3. 136 360.105

1. 42% 2. 461.1 3. 131-134 360.106

1. 93% 2. 426.1 3. 123-125 360.107

1. 26% 2. 454.1 3. 132-134 360.108

1. 12% 2. 479.1 3. 129-132 360.109

1. 67% 2. 410.1 3. 119-121 360.110

1. 71% 2. 412 3. 102 360.111

1. 64% 2. 440.1 3. 91-93 360.112

1. 79% 2. 412 3. 111-113 360.113

1. 20% 2. 440.1 3. 130 (DEC) 360.114

1. 61% 2. 438.1 3. 117-119 360.115

1. 61% 2. 440.1 3. 117-119 360.116

1. 81% 2. 452 3. 118 360.117

1. 65% 2. 466 3. 109

Examples 361-368.45

[1465] Following the procedure set forth in Example 261 but using thecommercially available amine in the table below and the cyclobutenedioneintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained. 1. Yield (%) Prep. 2. MH⁺ Ex.Amine Ex. Product 3. mp (° C.) 361

20

1. 57% 2. 422 3. 172.4 362

21

1. 53% 2. 408 3. 139.8 363

21

1. 70% 2. 374 3. 167.8-170.1 364

23

1. 21% 2. 334 3. 184.3 365

23

1. 61% 2. 348 3. 205.6 366

21.1

1. 75% 2. 344 3. 170-172 367

21.1

1. 66% 2. 330 3. 160-162 368

22

1. 31% 2. 436 3. 140-145 368.1

20

1.  8% 2. 374 3. 130-133 368.2

23.1

1. 56% 2. 372 3. 188-191 368.3

23.1

1. 67% 2. 406 3. 142-144 368.4

23.2

1. 69% 2. 408 3. 147-150 368.5

23.2

1. 67% 2. 374 3. 177-180 368.6

23.3

1. 45% 2. 385 3. 236-240 368.7

23.3

1. 35% 2. 425 3. 248-251 368.8

23.2

1. 66% 2. 414 3. 156-160 368.9

23.4

1. 78% 2. 428 3. 138-140 368.10

23.5

1. 46% 2. 428 3. 149-153 368.11

23.6

1. 54% 2. 412 3. 136-138 368.12

21

1. 30% 2. 414 3. 164-167 368.13

23.1

1. 25% 2. 412 3. 172-177 368.14

23.7

1. 21% 2. 434 3. 208-211 368.15

23.8

1. 27% 2. 478 3. 216-219 368.16

23.9

1. 63% 2. 400 368.17

23.9

1. 61% 2. 406.1 3. 127 DEC 368.18

23.9

1. 68% 2. 436.1 3. 128 DEC 368.19

23.9

1. 72% 2. 404.1 3. 126 DEC 368.20

23.10

1.  8.4% 2. 478 368.21

23.9

1. 39% 2. 432.1 3. 151-153 368.22

23.12

1. 78% 2. 414.1 3. 210 DEC 368.23

23.11

1.  4% 2. 504 368.24

23.11

1. 31% 2. 490 3. 241-245 368.25

23.9

1. 81% 2. 420.1 3. 126-128 368.26

23.11

1.  8% 2. 476 3. 193-198 368.27

23.9

1. 70% 2. 434.1 3. 130 DEC 368.28

23.11

1. 83% 2. 506 3. 222-227 368.29

23.11

1. 17% 2. 464 3. 183-190 368.30

23.13

1.  6.5% 2. 438.1 368.31

23.14

1. 71% 2. 471.1 3. 149-151 368.32

23.14

1. 58% 2. 471.1 3. 149 368.33

23.15A

1. 33% 2. 440.1 3. 181 368.34

23.15A

1. 56% 2. 468 3. 180 368.35

23.15A

1. 28% 2. 480 3. 186 368.36

23.15A

1. 48% 2. 494 3. 112.5 368.37

23.15B

1. 58% 2. 592 3. 177-179 368.38

23.15C

1. 69% 2. 516 3.  88-90 368.39

23.15D

1. 80% 2. 530 3. 134-137 368.40

23.15E

1. 57% 2. 454 3. 138-140 368.41

19.2

1. 26% 2. 507 3. 162-164 368.42 3 23.25

1. 82% 2. 466 3. 141-143 368.43 3 23.26

1. 67% 2. 480 3. 139 dec 368.44 13.29 23.16

1. 29% 2. 480 3. 112-114 368.45 13.29 23.26

1. 88% 2. 508 190 dec

Examples 369-378.23

[1466] Following the procedure set forth in Example 210 but using thecyclobutenedione intermediate from Preparative Example indicated and theamine from the Preparative Example indicated in the Table below, thefollowing cyclobutenedione products were obtained. Prep Ex of Cyclo-butene 1. Yield (%) Prep Ex of Inter- 2. MH⁺ Ex. Amine mediate Product3. mp (° C.) 369 8 87

1. 41% 2. 422 3. 135-140 370 9 87

1. 60% 2. 420 3. 120-125 371 10 87

1. 59% 2. 450 3. 162-167 372 12 87

1. 34% 2. 419 3. 157.2-168.2 373 12 88

1. 18% 2. 371 3. 1.42.3-144.6 374 13 87

1. 41% 2. 408 3. 245.3-247.8 375 5 87

1. 32% 2. 366 3. 165.7 376 6 87

1. 17% 2. 380 3. 173.5 377 7 87

1.48% 2. 436 3. 175.6 378

87

1.62% 2. 364 3. 155-160 378.1 3 88.3

1. 73% 2. 438.1 3. 116 378.2 3 88.2

1. 58% 2. 454 3. 140-142 378.3 13.3 87

1. 43% 2. 472 206-209 378.4 3 23.16

1. 69% 438.1 3. 116 378.5 3 23.17

1. 73% 2. 438.1 3. 116 378.6 13.4 87

1. 10% 2. 470 3. 198-201 DEC 378.7 13.5 87

1. 16% 2. 471 3. 246-248 378.8 13.3 23.16

1. 30% 2. 516/518 3. 234-240 DEC 378.9 13.19 23.16

1. 65% 2. 444.1 378.10 3 23.20

1. 78% 2. 488 3. 137-140 378.11

88.1

1. 24% 2. 371 3. 254-260 DEC 378.12 13.6 88.1

1.  3% 2. 542 378.13 13.7 88.1

1.  9% 2. 542 378.14

88.1

1. 48% 2. 434 3. 150-152 378.15 3 23.19

1. 71% 2. 488 3. 136-138 378.16 3 23.22

1. 35% 2. 424.1 3. 132 378.17 13.9 88.1

1. 13% 2. 440 3. 219-223 378.18 13.10 88.1

1. 25% 2. 406 3. 242-249 DEC 378.19 13.8 88.1

1. 18% 2. 395 378.20 3 23.18

1. 53% 2. 478.1 3. 126 378.21 3 23.21

1. 66% 2. 466 3. 106 378.22 3 23.24

1. 73% 2. 502.1 3. 121 378.23 3 23.23

1. 57% 2. 458.1 3. 129

Examples 378.25-378.89

[1467] Following the procedure set forth in Example 210 but using thecyclobutenedione intermediate from Preparative Example indicated and theamine from the Preparative Example indicated in the Table below, thefollowing cyclobutenedione products were obtained. Prep Ex of Cy- clo-bu- tene Inter- 1. Yield Prep Ex medi- (%) Ex. of Amine ate Product 2.MH⁺ 378.25 11.10 87.1

1. 71% 2. 480.0 378.26 10.28 87.1

1. 60% 2. 449.9 378.27 11.11 88.4

1. 25% 2. 540.1 [M +Na⁺] 378.28 10.36 87.1

1. 16% 2. 465.0 378.29 10.7 88.5

1. 46% 2. 440.4 378.30 10.9 88.4

1. 43% 2. 934.9 [dimer +1]³⁰ 378.31 11.12 88.4

1. 48% 2. 464.0 378.32 10.35 87.1

1. 17% 2. 437 378.33 10.8 87.1

1. 10% 2. 481.9 378.34 11.13 87.1

1. 55% 2. 463.9 378.35 10.29 87.1

1. 34% 2. 471.9 378.36 10.48 87.1

1.  4% 2. 433.9 378.36 A 10.10 87.1

1. 85% 2. 451.9 378.37 10.31 87.1

1. 36% 2. 423.8 378.38 10.17 87.1

1. 85% 2. 521.1 378.39 10.32 87.1

1. 63% 2. 409.9 378.40

87.1

1. 44% 2. 323.1 378.41 10.33 87.1

1. 20% 2. 486.0 378.42 10.13 87.1

1. 47% 2. 520.1 378.43 10.34 87.1

1. 18% 2. 449.9 378.44 11.14 87.1

1. 13% 2. 424.0 378.45 2.13 87.1

1. 13% 2. 423.8 378.46 12.1 87.1

1. 51% 2. 487.1 378.47 10.38 88.4

1. 72% 2. 437.7 378.48 11.15 87.1

1. 29% 2. 477.9 378.49 10.14 87.1

1. 61% 2. 560.2 378.50 11.18 87.1

1. 25% 2. 480.0 378.51 10.18 87.1

1. 51% 2. 466.0 378.52 12.2 87.1

1. 32% 2. 380.9 378.53 10.19 87.1

1. 14% 2. 461.4 378.54 11.1 87.1

1. 41% 2. 463.9 378.55 11.2 87.1

1.  5% 2. 409.9 378.56 10.20 87.1

1. 70% 2. 478.1 378.57 10.49 87.1

1. 17% 2. 421.9 378.58 10.15 87.1

1. 51% 2. 582.1 378.59 10.46 87.1

1. 18% 2. 477.9 378.60 11.16 88.4

1. 54% 2. 455.1 378.61 10.21 87.1

1. 84% 2. 485.9 378.62 10.40 87.1

1.  4% 2. 506.1 378.65 2.8 87.1

1. 34% 2. 480 378.66 10.22 87.1

1. 16% 2. 486.0 378.67 2.10 87.1

1. 44% 2. 545 378.68 10.23 87.1

1. 26% 2. 493.9 378.69 2.14 87.1

1. 60% 2. 437.9 378.70 10.24 87.1

1. 64% 2. 469.9 378.71 10.18 88.4

1. 64% 2. 471.1 378.72 10.39 88.4

1. 41% 2. 451.7 378.73 10.30 87.1

1. 60% 2. 464.0 378.74 10.25 87.1

1. 63% 2. 470.1 378.75 10.26 87.1

1. 10% 2. 448.0 378.76 10.50 87.1

1.  5% 2. 477.0 378.77 10.42 88.4

1. 57% 2. 467.7 378.78 11.17 87.1

1. 75% 2. 478.0 378.79 2.9 87.1

1. 21% 2. 561 378.80 10.43 87.1

1. 69% 2. 437.9 378.81 10.41 87.1

1.  3% 2. 436.0 378.82 10.44 87.1

1. 90% 2. 454.0 378.83 10.13 88.4

1. 29% 2. 524.1 378.84 10.45 88.4

1. 46% 2. 511.7 378.86 10.37 87.1

1. 53% 2. 452.0 378.88 10.47 87.1

1. 61% 2. 506.1 378.89 10.16 87.1

1. 30% 2. 568.1

Example 378.90

[1468]

[1469] The above compound from Preparative Example 378.68 was stirredwith 4N HCl/dioxane to yield the product (23%, MH+=437.9).

Example 378.91

[1470]

[1471] Using the procedure set forth in Preparative Example 2, Step A,but using Preparative Example 2.16 and Preparative Example 2.15, thetitle compound was prepared (20%, MH+=472.9).

Examples 379-393

[1472] Following the procedure set forth in Example 210 but using theamine from the Preparative Example indicated and the ethoxy squarateintermediate from Preparative Example 87, the following cyclobutenedioneproducts were obtained. 1. Yield (%) Ex. Aniline Product 2. (MH⁺) 379109

1. 29% 2. 436.0 380 105

1.  6.3% 2. 550.0 381 106

1. 12% 2. 557.0 382 107

1.  8.6% 2. 573.0 383 143

1.  3.2% 2. 497.0 384 135

1. 36% 2. 529.0 385 130

1. 33% 2. 506.1 387 145

1. 27% 2. 449.1 388 140

1. 25% 2. 477.0 389 98

1. 66% 2. 542.1 390 96

1. 60% 2. 545.0 391 97

1. 66% 2. 540.1 392 100

1. 47% 2. 512.1 393 99

1. 60% 2. 528.1

Examples 394-404.4

[1473] Following the procedure set forth in Example 261 but using theamines from the Preparative Examples indicated in the table below andthe cyclobutenedione derivative from Preparative Example 19, thefollowing cyclobutenedione products were obtained as racemicmixtures. 1. Yield (%) Prep Ex. 2. MH⁺ Ex. of Amine Product 3. mp (° C.)394 147

1. 64% 2. 358.1 3. 137 395 148

1. 23% 2. 372.1 3. 126 396 149

1. 94% 2. 386.1 3. 108 397 150

1. 86% 2. 386.1 3. 134 398 146

1. 87% 2. 420.1 3. 136 399 151

1. 84% 2. 434.1 3. 129 400 152

1. 90% 2. 372.1 3. 154 401 153

1. 86% 2. 386.1 3. 156 402 154

1. 90% 2. 400.1 3. 153 403 155

1. 91 2. 400.1 3. 153 404 156

1. 83% 2. 448.1 3. 138 404.1

1. 30% 2. 426.1 3. 132 404.2

1. 74% 2. 412.1 3. 127 404.3

1. 73.4% 2. 372.1 3. 128 404.4

1. 72% 2. 372.1 3. 128

Example 405

[1474]

[1475] To a solution of the amine from Preparative Example 75.1 (11.3 g)in EtOH (100 mL) at room temperature was added the product fromPreparative Example 19 (16.4 g) in one portion. The resulting mixturewas stirred at reflux overnight and then concentrated under reducedpressure. The crude residue was redissolved in CH₂Cl₂ (80 mL) and waswashed with 10% KH₂PO₄ (120 mL). The solid precipitate that wasgenerated was filtered, washed with water and dried under vacuo. Theresidue was recrystallized from methanol-methylene chloride to give acream colored solid (16 g, 75% yield). (mp 105-108° C., MH⁺ 398.1).

Examples 1101-1112.10

[1476] If one were to follow the procedure set forth in Example 210 butusing the ethoxysquarate from the Preparative Example indicated and theamines from the Preparative Example indicated in the Table below, thefollowing cyclobutenedione products can be obtained. Prep Ex of Prep Exof Ex. Amine Squarate Product 1101  15 87

1102  15 88

1103  16 87

1104  16 88

1105  17 87

1106  17 88

1107  18 87

1108  18 88

1109 157 87

1110 157 88

1111 158 87

1112 158 88

1112.1 500.3 or 500.4 88.1

1112.2 500.1 or 500.2 88.1

1112.3 500.5 19

1112.4  75.9 23.11

1112.5  10.19 88.4

1112.6  75.44 23.14

1112.7  75.49 23.14

1112.8  75.50 23.14

1112.9  75.44 500.6

1112.10  75.49 500.6

Examples 1120.1-1120.12

[1477] Following the procedure set forth in Example 210 but using theamine from the Preparative Example indicated and the ethoxy squarateintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained. Prep Ex 1. Yield (%) Prep Ex ofof 2. MH⁺ Ex. Amine Squarate Product 3. mp (° C.) 1120.1 156.16 87

1. 9% 2. 393.1 3. 154-158 1120.2

88.1

1. 55% 2. 355.1 3. 199-201 1120.3 156.12 88.1

1. 37% 2. 355.1 3. 210-213 1120.4

88.1

1. 30% 2. 391.1 3. 70-73 1120.5 156.14 88.1

1. 73% 2. 466 3. 105-108 1120.6

88.1

1. 21% 2. 391 3. 79-82 1120.7

88.1

1. 15% 2. 369 3. 167-170 1120.8

88.1

1. 47% 2. 354 3. 121-124 1120.9

88.1

1. 15% 2. 356 3. 200-202 1120.10

88.1

1. 25% 2. 468 3. 154-156 1120.11 156.13 88.1

1. 57% 2. 404 3. 92-94 1120.12 156.15 88.1

1. 61% 2. 351 3. 155-157

Example 1125

[1478]

[1479] Step A

[1480] If one were to use a similar procedure to that used inPreparative Example 13.3 Step B, except using the hydroxy acid fromBioorg. Med. Chem. Lett. 6(9), 1996, 1043, one would obtain the desiredmethoxy compound.

[1481] Step B

[1482] If one were to use a similar procedure to that used inPreparative Example 13.19 Step B, except using the product from Step Aabove , one would obtain the desired compound.

[1483] Step C

[1484] If one were to use a similar procedure to that used in Synth.Commun. 1980, 10, p. 107, except using the product from Step B above andt-butanol, one would obtain the desired compound.

[1485] Step D

[1486] If one were to use a similar procedure to that used in Synthesis,1986, 1031, except using the product from Step C above, one would obtainthe desired sulfonamide compound.

[1487] Step E

[1488] If one were to use a similar procedure to that used inPreparative Example 13.19 Step E, except using the product from Step Dabove, one would obtain the desired compound.

[1489] Step F

[1490] If one were to use a similar procedure to that used inPreparative Example 19, except using the product from Step E above andadding potassium carbonate as base, one would obtain the desiredcompound.

[1491] Step G

[1492] If one were to follow the procedure set forth in Example 210,except using the product from Step F above and the amine fromPreparative Example 75.9, then one would obtain the title compound.

Example 1130

[1493]

[1494] Step A

[1495] If one were to treat the product from Step C of Example 1125 withBuLi (2.2 eq.) in THF followed by quenching of the reaction mixture withN,N,-dimethylsulfamoyl chloride (1.1 eq.) then one would obtain

[1496] Step B

[1497] If one were to use the product of Step A above and one were tofollow Steps E, F and G of Example 1125, except using the amine fromPreparative Example 75.49 in Step G, then one would obtain the titlecompound.

Example 1131

[1498]

[1499] Step A

[1500] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. Themixture was stirred for 15 min at −78° C. and 1.5 h at room temp.Afterwards, the mixture was poured carefully into crushed ice, andextracted with dichloromethane. The extracts were washed with brine,dried over magnesium sulfate, filtered through a 1-in silica gel pad.The filtrate was concentrated in vacuo to give the desired compound (4.2g).

[1501] Step B

[1502] The product from Step A above (4.5 g) was dissolved indichloromethane (140 mL) and added with triethylamine (8.8 mL) followedby diethyl amine in THF (2M, 21 mL). The resulting mixture was stirredat room temperature overnight. The mixture was washed with brine andsaturated bicarbonate (aq) and brine again, dried over sodium sulfate,filtered through a 1-in silica gel pad. The filtrate was concentrated invacuo to give the desired compound (4.4 g).

[1503] Step C

[1504] The product from Step B above (4.3 g) was dissolved indichloromethane (125 mL) and cooled in a −78° C. bath. A solution ofboron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. Themixture was stirred for 4 h while the temperature was increased slowlyfrom −78° C. to 10° C. H₂O was added, the two layers were separated, andthe aqueous layer was extracted with dichloro-methane. The combinedorganic layer and extracts were washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 3.96 g of thedesired hydroxy-compound.

[1505] Step D

[1506] The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with brine, dried over sodiumsulfate, and filtered through a celite pad. The filtrate wasconcentrated in vacuo to afford 4.2 g of the desired bromo-compound.

[1507] Step E

[1508] The product from Step D (4.2 g) was dissolved in 100 mL ofacetone and added with potassium carbonate (10 g) followed byiodomethane (9 mL). The mixture was heated to reflux and continued for3.5 h. After cooled to room temperature, the mixture was filteredthrough a Celite pad. The filtrate was concentrated in vacuo to a darkbrown residue, which was purified by flash column chromatography elutingwith dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desiredproduct.

[1509] Step F

[1510] The product from step E (2.7 g) was converted to the desiredimine compound (3 g), following the similar procedure to that ofPreparative Example 13.19 step D.

[1511] Step G

[1512] The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH˜6 using 3.0 Mand 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

[1513] Step H

[1514] The product from step F (122 mg) was stirred withdiethyoxysquarate (0.25 mL) and potassium carbonate (75 mg) in 5 mL ofethanol at room temperature for 5 h. The mixture was diluted withdichloromethane, filtered through a Celite pad, and concentrated to anoily residue, which was separated by preparative TLC (CH₂Cl₂-M OH=15:1,v/v) to give 91 mg of the desired product.

[1515] Step I

[1516] Following the procedure set forth in Example 210, and using theamine from Preparative Example 75.9, the product (43 mg) from Step H wasconverted to the desired compound (20 mg).

Preparative Example 600

[1517]

[1518] Step A

[1519] Following the procedure set forth in Preparative Example 13.19Step D, the imine was prepared from the known bromoester (1.0 g) toyield 1.1 g (79%) as a yellow solid.

[1520] Step B

[1521] The product of step A (0.6 g) was reacted following the procedureset forth in Preparative Example 13.19 Step E to give the amine product0.19 g (64%).

[1522] Step C

[1523] The product of Step B (1.0 g) was reacted following the procedureset forth in Preparative Example 13.19 Step B to give the acid as yellowsolid 0.9 g (94%).

[1524] Step D

[1525] The product of Step C (0.35 g) was reacted following theprocedure set forth in Preparative Example 13.19 Step E to give theamino acid as yellow solid 0.167 g (93%).

Preparative Example 601

[1526]

[1527] Step A

[1528] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi(8.38 mL) at −78° C. and stirred at room temperature for half an hour.The reaction mixture again cooled to −78° C. and quenched withcyclopropyl amide 1 and stirred for two hours at −78° C. and slowlywarmed to room temperature. The reaction mixture stirred for three hoursat room temperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

[1529] Step B

[1530] To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL)at 0° C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene)dropwise followed by addition of a solution of borane complexed withdimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirredfor 30 minutes at 0° C. and than at room temperature for one hour. Thereaction mixture was cooled to 0° C. and MeOH was added carefully. Themixture was stirred for 20 minutes and was concentrated under reducedpressure. The residue was extracted with ether, washed with water, 1MHCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andremoval of solvent afforded the crude alcohol which was purified bysilica gel chromatography to afford the pure alcohol 0.91 g (91%) asyellow oil.

Preparative Example 602

[1531]

[1532] Step A

[1533] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours.After cooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

[1534] Step B

[1535] The title alcohol was obtained following a similar procedure setforth in Preparative Example 601.

Preparative Example 603

[1536]

[1537] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silica gelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 604-611

[1538] Following a similar procedure set forth in Preparative Examples13.25 or 601 the following Alcohols were prepared. Prep Ex FuranElectrophile Alcohol Yield 604

86% 605

69% 606

84% 607

82% 608

60% 609

65% 610

82% 611

89%

Preparative Examples 620-631

[1539] Following a similar procedure set forth in Preparative Examples13.25 the following Amines were prepared from the correspondingAlcohols. Prep Ex ALCOHOL AMINE % YIELD 620

28% 621

58% 622

69% 623

81% 624

82% 625

45% 626

57% 627

58% 628

54% 629

53% 630

50% 631

82

Preparative Examples 640-641

[1540] Following the procedures set forth in Preparative Example 19 butusing the amine from the Preparative Example indicated in the Tablebelow, the cyclobutenedione intermediates were obtained. Amine from 1.Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 640 600 Step B

1. 60% 2. 138 641 600 Step D

1. 66% 2. 138

Examples 1200-1211

[1541] Following the procedure set forth in Example 261 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the table below, the following cyclobutenedioneproducts were obtained. 1. Yield (%) 2. MH⁺ Ex. Amine Product 3. mp (°C.) 1200

1. 61.3% 2. 451.4 3. 108.6 1201

1. 54% 2. 439.5 3. 117.8 1202

1. 80% 2. 439.5 3. 128-131.8 1203

1. 75% 2. 423.4 3. 118-119 1204

1. 74% 2. 447.4 3. 108-111 1205

1. 42% 2. 415.42 3. 136-140 1206

1. 46% 2. 423.4 3. 114-117 1207

1. 35% 2. 433.1 3. 123-128 1208

1. 42% 2. 423.4 3. 118-121 1209

1. 51% 2. 415.4 3. 112-117 1210

1. 44% 2. 415.4% 3. 115-120 1211

1. 48% 2. 445.4 3. 105-110

Examples 1300-13011

[1542] Following the procedure set forth in Example 261 but using thecommercially available amine in the table below and the cyclobutenedioneintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained. 1. Yield (%) Prep. 2. MH⁺ Ex.Amine Ex. Product 3. mp (° C.) 1300

640

1. 35% 2. 390.4 3. 100 1301

641

1. 78% 2. 390.4 3. 130 1302

23.9

1. 48% 2. 483.4 3. 116 1303

23.9

1. 46% 2. 443.5 3. 106 1304

23.9

1. 40% 2. 445.54 3. 102 1305

23.9

1. 51% 2. 413.4 3. 98 1306

23.9

1. 78% 2. 405.5 3. 246 1307

23.9

1. 83% 2. 439.5 3. 129 1308

23.15A

1. 11% 2. 519.47 3. 123 1309

23.15A

1. 47% 2. 475 3. 113 1310

640

1. 55% 2. 496.1 3. 123-125 1311

640

1. 74% 2. 468.1 3. 116-118

Preparative Example 1001

[1543]

[1544] Step A

[1545] Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to amixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol)(prepared according to known method, see: EP0897904B1),N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) withstirring at rt. The reaction mixture was stirred overnight. Evaporationof solvent and excess oxalyl chloride and drying under vacuum afforded2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was usedwithout purification.

[1546] Step B

[1547] A solution of 2-methoxy-6-(trifluoromethyl)benzoyl chloride (ca.6.81 mmol) from Step A above in dichloromethane (20 mL) was addeddropwise to a mixture of 4-(dimethylamino)pyridine (42 mg, 0.34 mmol),triethylamine (2.8 mL, 20.09 mmol), and 2 M dimethylamine solution intetrahydrofuran (7 mL, 14 mmol), and dichloromethane (30 mL) withstirring at rt. The reaction mixture was stirred overnight. A mixture ofdichloromethane and water was added. The organic phase was separated,washed with 1N HCl solution, water, and saturated sodium bicarbonatesolution and concentrated. The residue was purified by columnchromatography (ethyl acetate:hexanes, 3:1 v/v) to give the product as awhite solid (1.24 g. 74% over two steps).

[1548] Step C

[1549] A mixture of the amide from Step B above (1.8 g, 7.28 mmol),carbon tetrachloride (25 mL), and iron powder (305 mg, 5.46 mmol) wascooled to 0° C. Bromine (0.94 mL, 18.34 mmol) was added dropwise withstirring. After addition, the mixture was stirred at rt for 1 h and at50° C. for 3 h. The mixture was cooled to rt, diluted withdichloromethane, and slowly poured to a cold 10% NaHSO₃ solution. Afterstirring at rt for 0.5 h, the organic layer was separated andconcentrated to give the product as a white solid (2.26 g, 95%).

[1550] Step D

[1551] Concentrated sulfuric acid (10 mL) was added dropwise to a flaskcharged with the bromide from Step C above (600 mg, 1.84 mmol) at 0° C.with stirring. A mixture of nitric acid (0.2 mL, 4.76 mmol) andconcentrated sulfuric acid (0.3 mL) was then added dropwise. Afteraddition, the mixture was stirred at rt for 3 h. The mixture was addedto ice-water, neutralized with 15% NaOH solution to pH 7, and extractedwith dichloromethane. The organic layer was concentrated to give theproduct as a white solid (621 mg, 91%). mp 92° C., m/e 371 (MH⁺).

[1552] Step E

[1553] A solution of the compound from Step D above (1.2 g, 3.23 mmol)in dichloromethane (50 mL) was cooled to −75° C. 1 M BBr₃ solution indichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. Themixture was stirred at −75° C. for 2 h. The mixture was added toice-water. After stirring at rt for 0.5 h, the mixture was extractedwith dichloromethane. The organic was concentrated and the residue waspurified by column chromatography (dichloromethane-methanol, 9:1 v/v) togive the product as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺).

[1554] Step F

[1555] A mixture of the compound from Step E above (1.08 g, 3.02 mmol),methanol (30 mL), and 10% Pd—C (250 mg) was subjected to hydrogenationat 50 psi at rt for 6 h. The mixture was filtered through a layer ofCelite. The filtrate was concentrated to give the title compound as apale yellow solid (930 mg, 96%). mp 132° C., m/e 249.

Preparative Example 1002

[1556]

[1557] Step A

[1558] To a cooled (−70° C.) etherial (45 mL dry) solution of3-bromothiophene (3.8 mL) was added BuLi (30 mL of 1.6M in hexane)dropwise, and the mixture was stirred at −70° C. for 20 min.Acetophenone (4.6 mL) in ether (6 mL) was added dropwise with stirringat 31 70° C. After 3 hrs, the mixture was warmed to RT and sat. NH₄Cl(aq) was added and the mixture was extracted with ether. The organicphase was dried (Na₂SO₄) and concentrated in vacuo to give the titlecompound which was used in Step B without further purification.

[1559] Step B

[1560] The crude product from Step A above was stirred with oxalic acid(0.375 g) at 70° C. under reduced pressure for 3 hr, then cooled to RTand extracted with ether. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give the product as a pale yellow liquid (5.7g, 78% for Steps A-B )

[1561] Step C

[1562] To the product from Step B above (4.2 g) diluted withdichloromethane (30 mL) and containing triethylsilane (6 mL) was addedTFA (3 mL) in dichloromethane (7.5 mL). After stirring at RT for 10 min,the mixture was concentrated in vacuo to give the product as a colorlessliquid (4.61 g, 80%).

[1563] Step D

[1564] To an etherial (3.5 mL dry) solution of the thiophene product(1.5 g) from Step C above was added BuLi (3.2 mL of 2.5M), and themixture was heated at reflux for 15 min, cooled to RT, and DMF (0.8 mL)in ether (3.5 mL) was added dropwise. After stirring for 30 min, sat.NH₄Cl (aq) was added and the mixture was extracted with ether. Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound (1.71 g, 98%).

Preparative Example 1003

[1565]

[1566] Step A

[1567] The aldehyde (0.50 g) was combined with ethylene glycol (1 mL),benzene (40 mL) and pTSA monohydrate (30 mg) and stirred at reflux for20 hr. Cool to room temperature, add EtOAc and sat. NaHCO₃ (aq)solution, separate the organic phase, concentrate in vacuo, and purifyby silica gel chromatography (EtOAc-Hex, 1:4) to give a colorless liquid(60 mg)

[1568] Step B

[1569] The product from Step A above (0.607 g) was stirred at 45° C.overnight with 1N NaOH (aq), then cooled to room temperature, acidifiedwith 3N HCl and extracted with EtOAc. Washing with brine andconcentration in vacuo gave a solid (5.0 g).

[1570] Step C

[1571] Following a similar procedure as that used in Preparative Example1, except using the product from Step B above and dimethylamine in THF(2M), the product was obtained (1.21 g crude).

[1572] Step D

[1573] The product from Step C above was dissolved in THF and stirredwith 0.3N HCl (aq) and stirred at RT for 4 hr. Concentration in vacuogave a pale yellow oil (1.1 g, 67%).

Preparative Example 1004

[1574]

[1575] Step A

[1576] To a cooled (−78° C.) solution of methoxybenzofuran-2-carboxylicacid (1 g) was added DIBAL (30 mL, 1M in THF). After stirring for 20min, the mixture was warmed to RT and stirred for 4 hr, then poured intosat. NH4Cl (aq) (35 mL). After stirring at RT for 20 min, 6M HCl (aq)was added and the mixture was extracted with EtOAc, the organic phasedried and then concentrated in vacuo. Purification by silica gelchromatography (EtOAc-hexane, 3:7) afforded the alcohol as a solid (0.4g, 97%).

[1577] Step B

[1578] A mixture of the product from Step A above (0.9 g), EtOAc (50 mL)and MnO2 (5.2 g) was stirred at RT for 22 h, then filtered andconcentrated in vacuo. The solid was redissolved in EtOAc (50 mL), MnO2(5.2 g) was added and the mixture was stirred for 4 additional hrs.Filtration, concentration and silica gel purification (EtOAc-Hexane,1:3) gave the title compound as a solid (0.60 g, 67%).

Preparative Example 1005

[1579]

[1580] Following a similar procedure as that detailed in PreparativeExample 1004, except using 5-chlorobenzofuran-2-carboxylic acid (1.5 g),the title compound was obtained (solid, 0.31 g, 24%).

Preparative Example 1006

[1581]

[1582] Step A

[1583] The sulfonyl chloride from Preparative Example 13.29 Step A (1.5g) was stirred with AlCl3 and benzene for 15 min at 20° C. Treatmentwith NaOH, extraction with Et₂O, concentration in vacuo, andpurification by column chromatography (silica, hexane-EtOAc, 5:2) gavethe phenylsulfone (1.5 g, 84%, MH⁺=255).

[1584] Step B

[1585] Following similar procedures as those used in Preparative Example13.29 Steps C-G, except using the sulfone from Step A above, the titlecompound was prepared (0.04 g, 27%, MH⁺=256).

Preparative Examples 1007-1029

[1586] Following a similar procedure set forth in Preparative Example19.1 of WO 02/083624, published Oct. 24, 2002, or Preparative Example19.2, but using the Amine (Anilines) listed in the Table below, thefollowing squarate intermediates were prepared. 1. Yield (%) ExampleAmine/Aniline Product 2. (M + 1)⁺ 1007

1. 95% 2. 359 1008

1. 99% 2. 333 1009

1. 99% 2. 333 1010

1. 99% 2. 311 1011

1. 99% 2. 275 1012

1. 99% 2. 333 1013

1. 72% 2. 353.0 1014

1. 60% 2. 355.1 1015

1. 70% 2. 303.1 1016

1. 45% 2. 327.0 1017

1. 70% 2. 367.0 1019

1. 32% 2. 409 1020

1. 48% 2. 466 1021

1. ˜60% (crude) 1022

1. 21% 1023

1. 45% 2. 389 1024

1. 30% 2. 380 1027

1. 44% 2. 264 1028

1. 56% 2. 278 1029

1. 47% 2. 292

Preparative Example 1030

[1587]

[1588] Step A

[1589] The product of Preparative Example 34.18 Step B (2 g, 8 mmol) wasstirred with morpholine (0.9 mL, 10.29 mmol) and K2CO3 (2.2 g, 15.9mmol) in 50 mL of acetone at RT to obtain the morpholinobutylfuranderivative (1.22 g,73%).

[1590] Step B

[1591] Following a similar procedure as in Preparative Example 34.18Step D, but using the product (1.2 g) from Step A above, the titlealdehyde was prepared (0.9 g,66%, 1:0.7 regioisomeric mixture).

Preparative Example 1031

[1592]

[1593] A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) inanhydrous-ether.(12 mL) was cooled to −78° C. 1.7 M tert-BuLi solutionin pentane (6 ml, 10.2 mmol) was added dropwise under argon. Afteraddition, the mixture was stirred at −78 ° C. for 20 min, followed byaddition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture wasallowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added.The mixture was poured to saturated ammonium chloride solution. Theorganic layer was separated and concentrated. The residue was purifiedby column chromatography (ethyl acetate-hexanes, 1:5 v/v) to give thetitle compound as a pale yellow solid (490 mg, 70%).

Preparative Examples 1040-1054

[1594] Following the procedure set forth in Preparative Example 64 of WO02/083624, published Oct. 24, 2002, but using the commercially available(or prepared) aldehyde, aminoalcohols, and organolithium reagents in theTable below, the optically pure amine products in the Table below wereobtained. Prep. Amino Organo- 1. Yield (%) Ex. Aldehyde Alcohol lithiumProduct 2. (M + 1)⁺ 1040

EtLi

1. 24% 2. 267 1041

EtLi

1. 94% 2. 176 (m/e) 1042

EtLi

1. 67% 2. 229 (M − 16) 1043

i-PrLi

1. 60% 2. 151 [M −16] 1044

EtLi

1. 74% 2. 194 (M − 16) 1045

EtLi

1. 33% 2. 165 [M −NH2]⁺ 1046

EtLi

1. 31 2. 179 [M −NH2]⁺ 1047

t-BuLi

1. 31% 2. 188 1048

t-BuLi

1. 10% 2. 154 1049

EtLi

1. 73% 2. 137 [M −NH2]⁺ 1051

t-BuLi

1. 17% 1054

t-BuLi

1. 79% 2. 151 (M − 16)

Preparative Examples 1100-1126

[1595] Following the procedure set forth in Preparative Example 34 of WO02/083624, published Oct. 24, 2002, but using the commercially availablealdehydes and Grignard/Organolithium reagents listed in the Table below,the amine products were obtained. Prep. Organo-metallic 1. Yield (%) Ex.Aldehyde Reagent Product 2. (M + 1)⁺ 1100

t-BuLi

1. 83% 2. 190 (M − 16) 1101

t-BuLi

1. 46% 2. 204 1102

t-BuLi

1. 48% 2. 194 1103

t-BuLi

1. 51% 2. 194 1104

t-BuLi

1. 12% 2. 238 1105

t-BuLi

1. 39% 2. 234 1106

t-BuLi

1. 44% 2. 194 (m/e) 1107

t-BuLi

1. 57% 2. 150 (M − 16) 1108

t-BuLi

1. 31% 2. 224 1109

t-BuLi

1. 11% 2. 224 1110

t-BuLi

1. 57% 2. 224 1111

t-BuLi

1. 21% 2. 224 1112

c-Pentyl-Li

1. 58% 2. 190 1113

t-BuLi

1. 20% 2. 248 1114

t-BuLi

1. 24% 2. 232 1115

EtLi

1. 32% 2. 177 (M −NH2) 1116

t-BuLi

1. 26% 2. 205 (M −NH2) 1117

t-BuLi

1. 50% 2. 190 (M −NH2) 1118

t-BuLi

1. 29% 2. 200 1119

t-BuLi

1. 28% 2. 232 1120

t-BuLi

1. 76% 2. 224 1121

t-BuLi

1. 40% 2. 206 1122

t-BuLi

1. 38% 2. 236 1123

t-BuLi

1. 70% 2. 192 1124

t-BuLi

1. 81% 2. 204 1125

t-BuLi

33% 1126

t-BuLi

50%

Preparative Examples 1200-1203

[1596] Following the procedure set forth in Preparative Example 13.29but using the commercially available amines, the hydroxyaminothiopheneproducts listed in the Table below were obtained. Prep. 1. Yield (%) Ex.Amine Product 2. (M + 1)⁺ 1200

1. 3% 2. 342 1201

1. 41% 2. 265 1202

1. 17% 2. 237 1203

1. 1%

Preparative Example 1300

[1597]

[1598] The title compound from Preparative Example 13.32 (0.35 g) wastreated with concentrated sulfuric acid (3 mL) for 6 hrs, then poured onice, and the pH adjusted to 4 with NaOH. Extraction with EtOAc, anddrying of the organic phase over Na₂SO₄ gave the title compound (159 mg,64%, MH⁺=223).

Preparative Example 1301

[1599]

[1600] Following the procedure set forth in Preparative Example 605 butusing the commercially available fluoroisopropylester, the alcoholproduct was obtained (1.2 g, 84%, M-OH=155).

[1601] Step B

[1602] Following the procedure set forth in Preparative Example 625 butusing the alcohol from Step A above, the amine product was obtained (350mg, 35%, M-NH2=155).

Preparative Example 1302

[1603]

[1604] Step A

[1605] Following a similar procedure as that used in Preparative Example13.29 Step B, except using the commercially availablearylsulfonylchloride (0.15 g) and diethylamine (2.2 eq), thedimethylsulfonamide was obtained (0.12 g, 71%, MH⁺=323).

[1606] Step B

[1607] Following a similar procedure as that used in Preparative Example13.29 Step C, except using the product from Step A above (0.12 g), thephenol was obtained (0.112 g, 98%).

[1608] Step C

[1609] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.112 g), the title compound was obtained(0.1 g, 99%, MH⁺=245).

Preparative Example 1303

[1610]

[1611] Following a similar procedure as that used in Preparative Example1302 Steps A-C, except using piperidine in Step A (0.078 g) instead ofdiethylamine, the title compound was obtained (0.070 g, 35%, MH⁺=257).

Preparative Example 1304

[1612]

[1613] Following a similar procedure as that used in Preparative Example1302 Steps A-C, except using dimethylamine (2M in THF) in Step A insteadof diethylamine, the title compound was obtained (1.92 g, 72%, MH⁺=217).

Preparative Example 1305

[1614]

[1615] Step A

[1616] Following a similar procedure as that used in Preparative Example1302 Step A, except using the phenethylamine indicated (4.99 g), theproduct was obtained (5.96 g, 86%, MH⁺=210).

[1617] Step B

[1618] The compound from Step A above (5.0 g) was added to 30 g of PPAat 150° C. and the resulting mixture stirred for 20 min, before beingpoured on ice and extracted with dichloromethane. The organic phase wasdried over MgSO4, concentrated in vacuo and purified by silica gelchromatography (EtOAc:MeOH, 95:5) to give the product (0.5 g, 9%).

[1619] Step C

[1620] Following a similar procedure as that used in Preparative Example13.3 Step D, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step B above (0.14 g), the product was obtained (0.18 g,87%, MH⁺=256).

[1621] Step D

[1622] Following a similar procedure as that used in Preparative Example11 Step B, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step C above (0.18 g), the product was obtained (0.17 g).

[1623] Step E

[1624] Following a similar procedure as that used in Preparative Example13.3 Step B, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step D above (0.17 g), the product was obtained (0.17 g,95%, MH⁺=315).

[1625] Step F

[1626] Following a similar procedure as that used in Preparative Example13.29 Step C, except using the product from Step E above (0.17 g), thenitrophenol was obtained (0.165 g, 99%, MH⁺=303).

[1627] Step G

[1628] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step F above (0.165 g), the title compound was obtained(0.128 g, 86%, MH⁺=193).

Preparative Example 1306

[1629]

[1630] Step A

[1631] Following a similar procedure as that used in Preparative Example11 Step B, of WO 02/083624, published Oct. 24, 2002, except using thelactam (0.179 g), the title compound was obtained (0.25 g, 25%).

[1632] Step B

[1633] Following a similar procedure as that used in Preparative Example13.29 Step C, except using the product from Step A above (0.055 g), thephenol was obtained (0.045 g, 99%).

[1634] Step C

[1635] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.045 g), the title compound was obtained(0.022 g, 57%, MH⁺=179).

Preparative Example 1307

[1636]

[1637] Following a similar procedure as that used in Preparative Example2, of WO 02/083624, published Oct. 24, 2002, except using3(R)-hydroxypyrrolidine HCl (1.36 g), the title compound was obtained(2.25 g, 89%).

Preparative Example 1308

[1638]

[1639] Following a similar procedure as that used in Preparative Example2, of WO 02/083624, published Oct. 24, 2002, except using morpholine,the title compound was obtained (3.79 g).

Preparative Example 1309

[1640]

[1641] Step A

[1642] Following a similar procedure as that used in Preparative Example13.29 Step B, except using the commercially availablenitrophenylsulfonylchloride and diethylamine (2.2 eq), thedimethylsulfonamide was obtained (90%, MH⁺=231).

[1643] Step B

[1644] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above, the title compound was obtained (45%,MH⁺=201).

Preparative Example 1310

[1645]

[1646] Step A

[1647] Following a similar procedure as that used in Preparative Example13.29 Step B, except using the commercially availablenitrobenzoylchloride and the commercially available amine indicated, thebenzamide was obtained (13%, MH⁺=253).

[1648] Step C

[1649] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above, the title compound was obtained (94%,MH⁺=223).

Preparative Example 1311

[1650]

[1651] Step A

[1652] To a benzene (20 mL) solution of methoxythiophenesulfonylchloride(1.5 g) was added AlCl₃ (2.0 g) at RT. After 15 min, the mixture wasadded to 0.1N HCl (aq) with stirring, then extracted with Et₂O. Washingthe organic phase with bring, drying over MgSO₄, concentration in vacuoand purification by silica gel chromatography (Hexane:EtOAc, 5:2) gavethe title compound (1.5 g, 84%).

[1653] Step B

[1654] Following a similar procedure as that used in Preparative Example13.29 Steps C-G, except using the product from Step A above, the titlecompound was obtained (3%, MH⁺=380).

Preparative Example 1312

[1655]

[1656] Step A

[1657] Following a similar procedure as that used in Preparative Example1311 Step A, except using the commercially available sulfonylchloride,the diphenylsulfone was obtained (880 mg, 80%).

[1658] Step B

[1659] Following a similar procedure as that used in Preparative Example11 Step B, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step A above, the title compound was obtained (0.90 g,97%).

[1660] Step C

[1661] Following a similar procedure as that used in Preparative Example10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.16 g), the title compound was obtained(0.106 g, 95%).

Preparative Example 1313

[1662]

[1663] Step A

[1664] Following a similar procedure as that used in Preparative Example1311 Step A, except using the commercially available phenol (2 g), thenitroacid was obtained (˜13 mmol).

[1665] Step B

[1666] Oxallyl chloride (3.5 mL) and two drops of DMF was added to theproduct from Step A above (˜13 mmol) dissolved in dichloromethane (100mL). After stirring at RT overnight, the mixture was concentrated invacuo, diluted with dichloromethane (50 mL), cooled to 0° C.Dimethylamine in THF (20 mL of 2N) and TEA (8 mL) were added. After 3 hrof stirring, the mixture was concentrated in vacuo, aq NaOH (1M) wasadded, and the mixture was extracted with dichloromethane. The pH of theaq is layer was adjusted to pH=2 using 6N HCl (aq), and extracted withdichloromethane. The combiuned organic extracts were washed with brine,dried, concentrated in vacuo, and the product purified by silica gelchromatography (700 mL dichloromethane/20 mL MeOH/1 mL AcOH) to give thetitle compound (800 mg, 27% for two steps).

[1667] Step C

[1668] Following a similar procedure as that used in Preparative Example10.55 Step C, WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (780 mg), the title compound was obtained(0.46 g, 68%).

Examples 2001-2088

[1669] Following a similar procedure set forth in Example 210, of WO02/083624, published Oct. 24, 2002, but using the cyclobutenedioneintermediate and amine indicated in the Table below, the followingcyclobutenedione products were obtained. See WO 02/083624, publishedOct. 24, 2002, for Preparative Examples 19, 19.2, 23.14 and 87.1. PrepEx of intermediate 1. Yield (%) Example and Amine Product 2. (M + 1)⁺2001 19 and

3. 65% 4. 465 2002 19 and

1. 5% 2. 422 2003 19 and

1. 47% 2. 462 2004 19 and

1. 74% 2. 452 2005 19 and

1. 71% 2. 452 2006 1007 and

1. 18% 2. 494 2007 19 and

1. 36% 2. 434 2008 19 and

1. 19% 2. 440 2009 19 and

1. 45% 2. 504 2010 19 and

1. 57% 2. 426 2011 19 and

1. 6% 2. 469 2012 19 and

1. 4% 2. 462 2013 19 and

1. 29% 2. 496 2014 19 and

1. 17% 2. 492 2015 1007 and

1. 65% 2. 466 2016 19 and

1. 72% 2. 452 2017 19 and

1. 22% 2. 412 2018 19 and

1. 5% 2. 425 2019 19 and

1. 82% 2. 482 2020 1008 and

1. 49% 2. 436 2021 22 and

1. 45% 2. 440 2022 19 and

1. 35% 2. 482 2024 1010 and

1. 16% 2. 414 2026 19 and

1. 46% 2. 482 2027 1010 and

1. 13% 2. 418 2028 1012 and

1. 39% 2. 440 2029 19 and

1. 55% 2. 382 2030 19 and

1. 39% 2. 378 2033 19 and

1. 71% 2. 482 2034 1013 and

1. 45% 2. 487.9 2035 1014 and

1. 22% 2. 461.8 2036 1015 and

1. 27% 2. 405.9 2037 87.1 and

1. 26% 2. 392.0 2038 1016 and

1. 28% 2. 433.8 2039 1017 and

1. 34% 2. 473.9 2040 19 and

1. 34% 2. 525 2041 23.15E and

1. 67% 2. 482 2042 1300 and 1027

1. 33% 2. 440 2043 1203 and 1027

1. 24% 2. 468 2044 19 and

1. 26% 2. 466 2046 19.2 and

1. 27% 2. 535 2047 23.15F and

1. 74% 2. 468 2048 23.15F and

1. 68% 2. 468 2049 19 and

1. 31% 2. 462 2050 23.15F and

1. 41% 2. 496 2051 19 and

1. 66% 2. 490 2052 19 and

1. 43% 2. 490 2053 19 and

1. 76% 2. 440 2054 1024 and

1. 15% 2. 473 2055 19 and

1. 87% 2. 454 2056 23.15F and

1. 52% 2. 516 2056A 23.15F and

1. 62% 2. 482 2057 23.15F and

1. 40% 2. 482 2058 23.15F and

1. 71% 2. 482 2059 1023 and

1. 67% 2. 482 2060 1023 and

1. 60% 2. 524 2061 19 and

1. 34% 2. 448 2062 19 and

1. 43% 2. 506 2063 19 and

1. 53% 2. 490 2064 19 and

1. 25% 2. 452 2065 19 and

1. 24% 2. 480 2066 19 and

1. 37% 2. 465 2067 19 and

1. 38% 2. 458 2068 19 and

1. 35% 2. 490 2069 19 and

1. 73% 2. 482 2070 19 and

1. 69% 2. 464 2071 19 and

1. 71% 2. 494 2072 1022 and

1. 54% 2. 467 2074 13.32A and 1028

1. 42% 2. 482 2075 19 and

1. 78% 2. 450 2076 19 and

1. 25% 2. 402

What is claimed is:
 1. A compound of the formula:

and the pharmaceutically acceptable salts and solvates thereof, wherein:A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

B is selected from the group consisting of:

provided that R³ for this group is selected from the group consistingof: —C(O)NR¹³R¹⁴.

n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R² is selectedfrom the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO₂NR¹³R¹⁴,—NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴, —C(O)NR¹³R¹⁴,—C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, an unsubstitutedheterocyclic acidic functional group, and a substituted heterocyclicacidic functional group; wherein there are 1 to 6 substituents on saidsubstituted heterocyclic acidic functional group each substituent beingindependently selected from the group consisting of: R⁹ groups; each R³and R⁴ is independently selected from the group consisting of: hydrogen,cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³,—C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³,—C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups; each R⁵ and R⁶ are the same or differentand are independently selected from the group consisting of hydrogen,halogen, alkyl, alkoxy, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³,—C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, cyano, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl group;wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups; each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, uansubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or moresubstituents on said substituted R⁷ and R⁸ groups, wherein eachsubstituent is independently selected from the group consisting of: a)halogen, b) —CF₃, c) —COR¹³, d) —OR¹³, e) —NR¹³R¹⁴, f) 13 O₂, g) —CN, h)—SO₂OR¹³, i) —Si(alkyl)₃, wherein each alkyl is independently selected,j) —Si(aryl)₃, wherein each alkyl is independently selected, k)—(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected, l) —CO₂R¹³, m)—C(O)NR¹³R¹⁴, n) —SO₂NR¹³R¹⁴, o) —SO₂R¹³, p) —OC(O)R¹³, q)—OC(O)NR¹³R¹⁴, r) —NR¹³C(O)R¹⁴, and s) —NR¹³CO₂R¹⁴; R^(8a) is selectedfrom the group consisting of: hydrogen, alkyl, cycloalkyl andcycloalkylalkyl; each R⁹ is independently selected from the groupconsisting of: a) —R¹³, b) halogen, c) —CF₃, d) —COR¹³, e) —OR¹³, f) —NR³R¹⁴, g) —NO₂, h) —CN, i) —SO₂R¹³, j) —SO₂NR ³R¹⁴, k) 'NR¹³COR¹⁴, l)—CONR¹³R¹⁴, m) —NR¹³CO₂R¹⁴, n) —CO₂R¹³, o)

p) alkyl substituted with one or more —OH groups, q) alkyl substitutedwith one or more —NR¹³R¹⁴ group, and r) —N(R¹³)SO₂R¹⁴; each R¹⁰ and R¹¹is independently selected from the group consisting of R¹³, hydrogen,alkyl (e.g., C₁ to C₆, such as methyl), halogen, —CF₃, —OCF₃, —NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³,—NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NROR¹³ OR¹⁴,—OC(O)R¹³ and cyano; R¹² is selected from the group consisting of:hydrogen, —C(O)OR¹³, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted arylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstitutedor substituted heteroarylalkyl group; wherein there are 1 to 6substituents on the substituted R¹² groups and each substituent isindependently selected from the group consisting of: R⁹ groups; each R¹³and R¹⁴ is independently selected from the group consisting of: H,unsubstituted or substituted alkyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedarylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl,unsubstituted or substituted heterocyclic, unsubstituted or substitutedfluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl(wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6substituents on said substituted R¹³ and R¹⁴ groups and each substituentis independently selected from the group consisting of: alkyl, —CF₃,—OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, halogen,and —NHC(O)NR¹⁵R¹⁶; or R¹³ and R¹⁴ taken together with the nitrogen theyare attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring, said ringoptionally containing one additional heteroatom selected from the groupconsisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents onthe substituted cyclized R¹³ and R¹⁴ groups and each substituent isindependently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and aheterocycloalkenyl group; each R¹⁵ and R¹⁶ is independently selectedfrom the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl andheteroaryl; R¹⁷ is selected from the group consisting of: —SO₂alkyl,—SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl; R¹⁸ is selected from thegroup consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰; each R¹⁹ and R²⁰ is independently selected from the groupconsisting of: alkyl, aryl and heteroaryl; R³⁰ is selected from thegroup consisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ providedthat R¹⁵ is not H; each R³¹ is independently selected from the groupconsisting of: unsubstituted alkyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl and unsubstituted or substitutedcycloalkyl; wherein there are 1 to 6 substituents on said substitutedR³¹ groups and each substituent is independently selected from the groupconsisting of: alkyl, halogen and —CF₃; each R⁴⁰ is independentlyselected from the group consisting of: H, alkyl and cycloalkyl; and t is0, 1 or
 2. 2. The compound of claim 1 wherein B is selected from thegroup consisting of:

provided that R³ for this group is selected from the group consistingof: —C(O)NR¹R¹⁴,


3. The compound of claim 1 wherein B is:

wherein R³ is selected from the group consisting of: —C(O)NR ¹³R¹⁴,


4. The compound of claim 1 wherein B is:


5. The compound of claim 1 wherein B is:

R² is —OH, and R¹³ and R¹⁴ are each the same or different alkyl group.6. The compound of claim 1 wherein B is

R³ is selected from the group consisting of:


7. The compound of claim 1 wherein B is:

and R² is —OH.
 8. The compound of claim 1 wherein B is

R¹³ and R¹⁴ are each the same or different alkyl group.
 9. The compoundof claim 1 wherein B is


10. The compound of claim 9 wherein R² is —OH.
 11. The compound of claim9 wherein R¹³ and R¹⁴ are the same or different alkyl group.
 12. Thecompound of claim 11 wherein the R² substituent is —OH.
 13. The compoundof claim 11 wherein R¹³ and R¹⁴ methyl.
 14. The compound of claim 13wherein the R² substituent is —OH.
 15. The compound of claim 1 wherein Bis selected from the group consisting of:


16. The compound of claim 1 wherein B is


17. The compound of claim 16 wherein R¹¹ is H.
 18. The compound of claim16 wherein R² is —OH.
 19. The compound of claim 16 wherein R³ is—C(O)NR¹³R¹⁴.
 20. The compound of claim 16 wherein R² is —OH and R³ is—C(O)NR¹³R¹⁴.
 21. The compound of claim 16 wherein R² is —OH, R³ is—C(O)NR¹³R¹⁴, and R¹¹ is H.
 22. The compound of claim 21 wherein R¹³ andR¹⁴ are each independently selected from the group consisting of: alkyl,unsubstituted heteroaryl and substituted heteroaryl.
 23. The compound ofclaim 16 wherein R³ is —S(O)_(t)NR ¹³R¹⁴.
 24. The compound of claim 23wherein R² is —OH.
 25. The compound of claim 24 wherein the R¹³ and R¹⁴substituents are the same or different and are selected from the groupconsisting of: H and alkyl.
 26. The compound of claim 25 wherein eachR¹³ and R¹⁴ are independently selected from the group consisting of: H,methyl, ethyl, isopropyl and t-butyl.
 27. The compound of claim 26wherein R¹³ and R¹⁴ are ethyl.
 28. The compound of claim 1 wherein B is


29. The compound of claim 1 wherein B is


30. The compound of claim 1 wherein A is

wherein the furan ring is unsubstituted or substituted.
 31. The compoundof claim 1 wherein A is

wherein the furan ring is substituted.
 32. The compound of claim 1wherein A is

wherein the furan ring is substituted with at least one alkyl group. 33.The compound of claim 30 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 34. The compound of claim 33wherein R⁷ is H, and R⁸ is alkyl.
 35. The compound of claim 32 whereinR⁷ and R⁸ are independently selected from the group consisting of: H andalkyl.
 36. The compound of claim 35 wherein R⁷ is H, and R⁸ is alkyl.37. The compound of claim 1 wherein A is selected from the groupconsisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and R⁸ais as defined for formula IA.
 38. The compound of claim 4 wherein A is

wherein the furan ring is unsubstituted or substituted.
 39. The compoundof claim 4 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 40.The compound of claim 39 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 41. The compound of claim 40wherein R⁷ is H and R⁸ is alkyl.
 42. The compound of claim 5 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 43. The compoundof claim 42 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 44.The compound of claim 43 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 45. The compound of claim 44wherein R⁷ is H and R⁸ is alkyl.
 46. The compound of claim 9 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 47. The compoundof claim 9 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 48.The compound of claim 47 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 49. The compound of claim 48wherein R⁷ is H and R⁸ is alkyl.
 50. The compound of claim 10 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 51. The compoundof claim 10 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 52.The compound of claim 51 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 53. The compound of claim 52wherein R⁷ is H and R⁸ is alkyl.
 54. The compound of claim 12 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 55. The compoundof claim 12 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 56.The compound of claim 55 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 57. The compound of claim 56wherein R⁷ is H and R⁸ is alkyl.
 58. The compound of claim 1 wherein:(1) A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA; (2) B is:

and wherein: R² is selected from the group consisting of: H, OH,—NHC(O)R¹³ and —NHSO₂R¹³; R⁴ is selected from the group consisting of:H, —NO₂, cyano, —CH₃ or —CF₃; R⁵ is selected from the group consistingof: H, —CF₃, —NO₂, halogen and cyano; and R⁶ is selected from the groupconsisting of: H, alkyl and —CF₃; and each R¹³ and R¹⁴ is independentlyselected from the group consisting of: methyl and ethyl.
 59. Thecompound of claim 1 wherein: (1) A is selected from the group consistingof:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA; (2) B is selected:

wherein: R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³; R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³; R¹¹ is selected fromthe group consisting of: H, halogen and alkyl; and each R¹³ and R¹⁴ isindependently selected from the group consisting of: H, methyl, ethyl,isopropyl, and t-butyl.
 60. The compound of claim 1 wherein: (1) A isselected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA; (2) B is selected:

wherein: R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³; R³ is —SO₂NR¹³R¹⁴; R¹¹ is selected from the groupconsisting of: H, halogen and alkyl; and each R¹³ and R¹⁴ isindependently selected from the group consisting of: H, methyl, ethyl,isopropyl, and t-butyl.
 61. The compound of claim 1 wherein: (1) A isselected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA; (2) B is selected:

wherein: R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³; R³ is —SO₂NR¹³R¹⁴; R¹¹ is selected from the groupconsisting of: H, halogen and alkyl; and each R¹³ and R¹⁴ is ethyl. 62.The compound of claim 1 wherein (1) A is selected from the groupconsisting of:

wherein: R² is —OH; R⁴ is selected form the group consisting of: H, —CH₃and —CF₃; R⁵ is selected from the group consisting of: H and cyano; R⁶is selected from the group consisting of: H, —CH₃ and —CF₃; R¹³ and R¹⁴are methyl.
 63. The compound of claim 1 wherein (1) A is selected fromthe group consisting of:

wherein: R²is —OH; R³ is selected from the group consisting of:—SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴; R¹¹ is H; and each R¹³ and R¹⁴ areindependently selected from the group consisting of: H, methyl, ethyl,isopropyl and t-butyl.
 64. The compound of claim 1 wherein (1) A isselected from the group consisting of:

wherein: R² is —OH; R³ is —SO₂NR¹³R¹⁴; R¹¹ is H; and each R¹³ and R¹⁴are independently selected from the group consisting of: H, methyl,ethyl, isopropyl and t-butyl.
 65. The compound of claim 1 wherein (1) Ais selected from the group consisting of:

wherein: R²is —OH; R³ is —SO₂NR¹³R¹⁴; R¹¹ is H; and R¹³ and R¹⁴ areethyl.
 66. The compound of claim 1 wherein said compound is a calciumsalt.
 67. The compound of claim 1 wherein said compound is a sodiumsalt.
 68. The compound of claim 1 wherein said compound is selected fromthe group consisting of:


69. The compound of claim 1 selected from the group consisting of:


70. The compound of claim 1 selected from the group consisting of:


71. The compound of claim 1 selected from the group consisting of:


72. The compound of claim 71 wherein said compound is a calcium orsodium salt.
 73. The compound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 74. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 75. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 76. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 77. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 78. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 79. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 80. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 81. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 82. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 83. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 84. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 85. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 86. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 87. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 88. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 89. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 90. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 91. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 93. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 94. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 95. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 96. Thecompound of claim 1 selected from the group consisting of the finalcompounds of Examples 1 to
 2088. 97. The compound of claim 96 whereinsaid compound is a calcium or sodium salt of a final compound ofExamples 1 to
 2088. 98. The compound of claim 1 selected from the groupconsisting of the final compounds of Examples 2006, 2010, 2015, 2029,2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079 and
 2087. 99. Thecompound of claim 98 wherein said compound is a calcium or sodium saltof a final compound of Examples 2006, 2010, 2015, 2029, 2034, 2035,2038, 2039, 2047, 2050, 2074, 2079 and
 2087. 100. The compound of claim83 wherein said compound is a calcium or sodium salt.
 101. The compoundof claim 84 wherein said compound is a calcium or sodium salt.
 102. Thecompound of claim 85 wherein said compound is a calcium or sodium salt.103. A pharmaceutical composition comprising an effective amount of acompound of claim 1 in combination with a pharmaceutically acceptablecarrier.
 104. A method of treating a chemokine-mediated disease, in apatient in need of such treatment, wherein the chemokine binds to aCXCR2 and/or CXCR1 receptor in said patient, comprising administering tosaid patient an effective amount of at least one compound of claim 1.105. A method of treating a chemokine-mediated disease, in a patient inneed of such treatment, wherein the chemokine binds to a CXC receptor insaid patient, comprising administering to said patient an effectiveamount of at least one compound of claim
 1. 106. The method of claim 104wherein the chemokine mediated disease is selected from the groupconsisting of: acute inflammatory pain, chronic inflammatory pain, acuteneuropoathic pain, chronic neuropathic pain, acute inflammation,rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adultrespiratory disease, arthritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, cardiac and renalreperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease,graft vs. host reaction, allograft rejections, malaria, acuterespiratory distress syndrome, delayed type hypersensitivity reaction,atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiplesclerosis, restinosis, angiogenesis, osteoporosis, gingivitis,respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi'ssarcoma associated virus, meningitis, cystic fibrosis, pre-term labor,cough, pruritis, multi-organ dysfunction, trauma, strains, sprains,contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis,traumatic brain injury, CNS tumors, subarachnoid hemorrhage, postsurgical trauma, interstitial pneumonitis, hypersensitivity, crystalinduced arthritis, acute and chronic pancreatitis, acute alcoholichepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenicocular disease, ocular inflammation, retinopathy of prematurity,diabetic retinopathy, macular degeneration with the wet type preferredand corneal neovascularization, polymyositis, vasculitis, acne, gastricand duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis,bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough,dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia,hyperoxia-induced inflammations, hypoxia, surgical lung volumereduction, pulmonary fibrosis, pulmonary hypertension, right ventricularhypertrophy, peritonitis associated with continuous ambulatoryperitoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis,small airway disease, ventilation-perfusion mismatching, wheeze, colds,gout, alcoholic liver disease, lupus, burn therapy, periodontitis,transplant reperfusion injury and early transplantation rejection, andchronic inflammation.
 107. A method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of at least one compound of claim
 1. 108. A method oftreating cancer in a patient in need of such treatment comprisingadministering to said patient an effective amount of at least onecompound of claim 1 in combination with the administration of at leastone anticancer agent.
 109. The method of claim 108 wherein saidanticancer agent is selected from the group consisting of: alkylatingagents, antimetabolites, natural products and their derivatives,hormones, anti-hormones, anti-angiogenic agents and steroids, andsynthetics.
 110. A method of inhibiting angiogenesis in a patient inneed of such treatment comprising administering to said patient aneffective amount of at least one compound of claim
 1. 111. A method ofinhibiting angiogenesis in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone compound of claim 1 in combination with the administration aneffective amount of at least one anti-angiogenesis compound.
 112. Amethod of treating a disease selected from the group consisting of:gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV,kaposi's sarcoma associated virus and atherosclerosis, in a patient inneed of such treatment, comprising administering to said patient aneffective amount of at least one compound of claim
 1. 113. The method ofclaim 112 wherein the chemokine mediated disease is an angiogenic oculardisease.
 114. The method of claim 113 wherein said angiogenic oculardisease is selected from the group consisting of: ocular inflammation,retinopathy of prematurity, diabetic retinopathy, macular degenerationwith the wet type preferred and corneal neovascularization.
 115. Themethod of claim 107 wherein the cancer treated is melanoma, gastriccarcinoma, or non-small cell lung carcinoma.
 116. The method of claim108 wherein the cancer treated is melanoma, gastric carcinoma, ornon-small cell lung carcinoma.
 117. The method of claim 109, wherein thecancer treated is melanoma, gastric carcinoma, or non-small cell lungcarcinoma.
 118. The method of claim 106 wherein said disease is COPD.119. The method of claim 106 wherein said disease is acute inflammation.120. The method of claim 106 wherein said disease is rheumatoidarthritis.
 121. The method of claim 106 wherein said disease is acuteinflammatory pain.
 122. The method of claim 106 wherein said disease ischronic inflammatory pain.
 123. The method of claim 106 wherein saiddisease is acute neuropathic pain.
 124. The method of claim 106 whereinsaid disease is chronic neuropathic pain.
 125. A method of treating achemokine-mediated disease, in a patient in need of such treatment,wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in saidpatient, comprising administering to said patient an effective amount ofat least one compound of formula IA:

and the pharmaceutically acceptable salts and solvates thereof, wherein:A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R² is selectedfrom the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO₂NR¹³R¹⁴,—NHC(O)R¹⁴³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴, —C(O)NR¹³R¹⁴,—C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, an unsubstitutedheterocyclic acidic functional group, and a substituted heterocyclicacidic functional group; wherein there are 1 to 6 substituents on saidsubstituted heterocyclic acidic functional group each substituent beingindependently selected from the group consisting of: R⁹ groups; each R³and R⁴ is independently selected from the group consisting of: hydrogen,cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³,—C(O)OR¹³, —C(O)NHR¹⁷, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³O R¹⁴,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl; wherein there are 1 to 6 substituents on said substitutedaryl group and each substituent is independently selected from the groupconsisting of: R⁹ groups; and wherein there are 1 to 6 substituents onsaid substituted heteroaryl group and each substituent is independentlyselected from the group consisting of: R⁹ groups; each R⁵ and R⁶ are thesame or different and are independently selected from the groupconsisting of hydrogen, halogen, alkyl, alkoxy, —CF₃, —OCF₃, —NO₂,—C(O)R¹³, —C(O)OR¹³, —C(O)NR ¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —C(O)NR ¹³OR¹⁴,cyano, unsubstituted or substituted aryl, and unsubstituted orsubstituted heteroaryl group; wherein there are 1 to 6 substituents onsaid substituted aryl group and each substituent is independentlyselected from the group consisting of: R⁹ groups; and wherein there are1 to 6 substituents on said substituted heteroaryl group and eachsubstituent is independently selected from the group consisting of: R⁹groups; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more substituents on saidsubstituted R⁷ and R⁸ groups, wherein each substituent is independentlyselected from the group consisting of: a) halogen, b) —CF₃, c) —COR¹³,d) —OR¹³, e) —NR¹³R¹⁴, f) —NO₂, g) —CN, h) —SO₂OR¹³, i) —Si(alkyl)₃,wherein each alkyl is independently selected, j) —Si(aryl)₃, whereineach alkyl is independently selected, k) —(R¹³)₂R¹⁴Si, wherein each R¹³is independently selected, l) —CO₂R¹³, m) —C(O)NR ³R¹⁴, n) —SO₂NR¹³R¹⁴,o) —SO₂R¹³, p) —OC(O)R¹³, q) —OC(O)NR¹³R¹⁴, r) —NR¹³C(O)R¹⁴, and s)—NR¹³CO₂R¹⁴; R^(8a) is selected from the group consisting of: hydrogen,alkyl, cycloalkyl and cycloalkylalkyl; each R⁹ is independently selectedfrom the group consisting of: a) —R¹³, b) halogen, c) —CF₃, d) —COR¹³,e) —OR¹³, f) —NR¹³R¹⁴, g) —NO₂, h) —CN, i) —SO₂R¹³, j) —SO₂NR¹³R¹⁴, k)—NR¹³COR¹⁴, l) —CONR¹³R¹⁴, m) —NR¹³CO₂R¹⁴, n) —CO₂R¹³, o)

p) alkyl substituted with one or more —OH groups, q) alkyl substitutedwith one or more —NR¹³R¹⁴ group, and r) —N(R¹³)SO₂R¹⁴; R¹² is selectedfrom the group consisting of: hydrogen, —C(O)OR¹³, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted alkyl, unsubstituted or substitutedcycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;wherein there are 1 to 6 substituents on the substituted R¹² groups andeach substituent is independently selected from the group consisting of:R⁹ groups; each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl; wherein there are 1 to 6 substituentson said substituted R¹³ and R¹⁴ groups and each substituent isindependently selected from the group consisting of: alkyl, —CF₃, —OH,alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, halogen,and —NHC(O)NR¹⁵R¹⁶; or R¹³ and R¹⁴ taken together with the nitrogen theyare attached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring, said ring optionally containing one additionalheteroatom selected from the group consisting of: O, S and NR¹⁸; whereinthere are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴groups and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶,—NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group; each R¹⁵ and R¹⁶is independently selected from the group consisting of: H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl; R¹⁷ is selected from the groupconsisting of: —SO₂alkyl, —SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl;R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; each R¹⁹ and R²⁰ isindependently selected from the group consisting of: alkyl, aryl andheteroaryl; each R⁴⁰ is independently selected from the group consistingof: H, alkyl and cycloalkyl; and t is 0, 1 or
 2. 126. The method ofclaim 125 wherein the chemokine mediated disease is selected from thegroup consisting of: acute inflammatory pain, chronic inflammatory pain,acute neuropoathic pain, chronic neuropathic pain, acute inflammation,rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adultrespiratory disease, arthritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, cardiac and renalreperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease,graft vs. host reaction, allograft rejections, malaria, acuterespiratory distress syndrome, delayed type hypersensitivity reaction,atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiplesclerosis, restinosis, angiogenesis, osteoporosis, gingivitis,respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi'ssarcoma associated virus, meningitis, cystic fibrosis, pre-term labor,cough, pruritis, multi-organ dysfunction, trauma, strains, sprains,contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis,traumatic brain injury, CNS tumors, subarachnoid hemorrhage, postsurgical trauma, interstitial pneumonitis, hypersensitivity, crystalinduced arthritis, acute and chronic pancreatitis, acute alcoholichepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenicocular disease, ocular inflammation, retinopathy of prematurity,diabetic retinopathy, macular degeneration with the wet type preferredand corneal neovascularization, polymyositis, vasculitis, acne, gastricand duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis,bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough,dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia,hyperoxia-induced inflammations, hypoxia, surgical lung volumereduction, pulmonary fibrosis, pulmonary hypertension, right ventricularhypertrophy, peritonitis associated with continuous ambulatoryperitoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis,small airway disease, ventilation-perfusion mismatching, wheeze, colds,gout, alcoholic liver disease, lupus, burn therapy, periodontitis,transplant reperfusion injury and early transplantation rejection, andchronic inflammation.
 127. The method of claim 125 wherein saidchemokine-mediated disease is cancer.
 128. The method of claim 127wherein the compound of formula IA is administered in combination withthe administration of at least one anticancer agent.
 129. The method ofclaim 128 wherein said anticancer agent is selected from the groupconsisting of: alkylating agents, antimetabolites, natural products andtheir derivatives, hormones, anti-hormones, anti-angiogenic agents andsteroids, and synthetics.
 130. The method of claim 125 whereinangiogenesis is inhibitied.
 131. The method of claim 130 wherein thecompound of formula IA is administered in combination with theadministration of an effective amount of at least one anti-angiogenesiscompound.
 132. The method of claim 125 wherein said chemokine-mediateddisease is selected from the group consisting of: gingivitis,respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi'ssarcoma associated virus and atherosclerosis.
 133. The method of claim125 wherein the chemokine mediated disease is an angiogenic oculardisease.
 134. The method of claim 133 wherein said angiogenic oculardisease is selected from the group consisting of: ocular inflammation,retinopathy of prematurity, diabetic retinopathy, macular degenerationwith the wet type preferred and corneal neovascularization.
 135. Themethod of claim 127 wherein the cancer treated is melanoma, gastriccarcinoma, or non-small cell lung carcinoma.
 136. The method of claim128 wherein the cancer treated is melanoma, gastric carcinoma, ornon-small cell lung carcinoma.
 137. The method of claim 129, wherein thecancer treated is melanoma, gastric carcinoma, or non-small cell lungcarcinoma.
 138. The method of claim 106 wherein said disease is chronicinflammation.
 139. The method of claim 125 wherein said disease is COPD,acute inflammation, chronic inflammation, rheumatoid arthritis, acuteinflammatory pain, chronic inflammatory pain, acute neuropathic pain,chronic neuropathic pain.
 140. The method of claim 106 wherein saidcompound is:


141. The method of claim 140 wherein said disease is selected from thegroup consisting of: COPD, rheumatoid arthritis, acute inflammation,chromic inflammation, acute inflammatory pain, chronic inflammatorypain, acute neuropathic pain, and chronic neuropathic pain.
 142. Themethod of claim 141 wherein said disease is COPD.
 143. The method ofclaim 141 wherein said disease is rheumatoid arthritis.
 144. The methodof claim 141 wherein said disease is acute inflammation or chronicinflammation.
 145. The method of claim 141 wherein said disease isselected from the group consisting of: acute inflammatory pain, chronicinflammatory pain, acute neuropathic pain and chronic neuropathic pain.146. The method of claim 106 wherein said compound is:


147. The method of claim 146 wherein said disease is selected from thegroup consisting of: COPD, rheumatoid arthritis, acute inflammation,chromic inflammation, acute inflammatory pain, chronic inflammatorypain, acute neuropathic pain, and chronic neuropathic pain.
 148. Themethod of claim 146 wherein said disease is COPD.
 149. The method ofclaim 146 wherein said disease is rheumatoid arthritis.
 150. The methodof claim 146 wherein said disease is acute inflammation or chronicinflammation.
 151. The method of claim 146 wherein said disease isselected from the group consisting of: acute inflammatory pain, chronicinflammatory pain, acute neuropathic pain and chronic neuropathic pain.152. The method of claim 106 wherein said compound is:


153. The method of claim 152 wherein said disease is selected from thegroup consisting of: COPD, rheumatoid arthritis, acute inflammation,chromic inflammation, acute inflammatory pain, chronic inflammatorypain, acute neuropathic pain, and chronic neuropathic pain.
 154. Themethod of claim 152 wherein said disease is COPD.
 155. The method ofclaim 152 wherein said disease is rheumatoid arthritis.
 156. The methodof claim 152 wherein said disease is acute inflammation or chronicinflammation.
 157. The method of claim 152 wherein said disease isselected from the group consisting of: acute inflammatory pain, chronicinflammatory pain, acute neuropathic pain and chronic neuropathic pain.